CN102656163A

CN102656163A - Heterocyclic compounds for the inhibition of PASK

Info

Publication number: CN102656163A
Application number: CN2010800497902A
Authority: CN
Inventors: J·M·麦考尔; J·麦基尔恩; D·L·罗梅罗; M·克莱尔
Original assignee: Bioenergenix LLC
Current assignee: Bioenergenix LLC
Priority date: 2009-09-03
Filing date: 2010-09-02
Publication date: 2012-09-05
Anticipated expiration: 2030-09-02
Also published as: WO2011028947A3; JP5696856B2; US20120165318A1; JP2013503896A; NZ598294A; MX2012002274A; ZA201201133B; DK2473504T3; WO2011028947A2; CN102656163B; US20160229815A1; KR20120095356A; US8916560B2; US9193693B2; IL218292A; CA2772714C; AU2010289397A1; EA201290078A1; EP2473504B1; KR101650981B1

Abstract

Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.

Description

The heterogeneous ring compound that suppresses PASK

The right of priority that No. the 61/239th, 744, the U.S. Provisional Application that the application requires to submit on September 3rd, 2009, its content is included this paper by reference in, as it is listed in this paper in full.

This paper discloses new heterogeneous ring compound and compsn and is used as the application of treatment disease medicament.Also be provided in human or animal's object and suppress the active method of PAS kinases (PASK) and be used to treat disease such as mellitus.

Glycogen Metabolism is regulated keeping Mammals glucose and energy homeostasis very crucial.Glycogen is big branched glucose polymer, in various organisms, is used as the deposit of carbon and energy.In the Mammals, most important storage is found in (1) in liver and the Skelettmuskel.Liver starch is that effectively buffering glucose level institute is essential during the fasting, and muscle glycogen is mainly used in the fuel (2) of local Muscle contraction.The Glycogen Metabolism dysregulation relates to the generation of numerous disease, comprises diabetes B (3,4).

The synthetic main adjusting glycogen synthetase (GYS, various isotypes) that passes through of glycogen is controlled, and a large amount of glycogens of its catalysis synthesize (5,6,7).The muscle isotype (GYS1) of glycogen synthetase is inactivation (8,9,10) through the reversible phosphorylation of 9 different positions generations in this enzyme.In the best forms of characterization of glycogen synthetase, said phosphorylation position bunch collection is at N and C end (14).Glycogen synthase kinase-3 (GSK-3) is the insulin-dependent kinases; The progressively phosphorylation that relates to 4 key positions of glycogen synthetase C end for a long time; Comprise Ser-640 (one of most important endogenous adjusting phosphorylation position (15,32) in the Mammals glycogen synthetase) and Ser-644 (10,11-13; 24,25).Yet GSK-3 is not unique kinases of phosphorylation C end adjusting position; Also there is GSK-3 independence mechanism, because the Serine on Ser-7 and the Ser-10-blocked important adjusting position Ser-640 that GSK-3 mediates and the phosphorylation of Ser-644 to the replacement of-L-Ala, and the phosphorylation of these positions still exists.

PASK (purine analogue susceptibility kinases, PAS kinases) is the serine/threonine kinase that contains the PAS structural domain, and the experiment of the gene in the yeast saccharomyces cerevisiae (S.cerevisiae) shows the physiology regulator (16,17) of PASK as glycogen synthetase and glycogen accumulation.The same with complete glycogen synthetase regulation system, PASK from yeast to people's high conservative.People PASK (hPASK) causes approaching deactivation completely mainly at Ser-640 phosphorylation glycogen synthetase.Notice that very enjoyably the definite position of PASK dependency phosphorylation is in yeast and Mammals glycogen synthetase similar but inequality (18,19); Yeast PASK is at the C of the position of similar Ser-644,4 residues end phosphorylation glycogen synthetase (18).As if hPASK region intermediate (residue 444-955) be external available phosphorus acidifying glycogen synthetase and with the former synthetic enzyme of endocellular sugar interact essential: the hPASK two mutants (Δ 955) of shortage non-catalytic N-terminal can not available phosphorus acidifying glycogen synthetase.Because this zone is not that the common non-physiology substrate of phosphorylation such as histone and synthetic peptide institute are essential, so it is very crucial to the substrate target to propose the region intermediate of hPASK.In many protein kinases, found similar substrate zone (26-29).Be different from GSK-3, show that the activity of hPASK is independent of Regular Insulin and possibly regulates (23) by more directly metabolic signals.

Gene that carries out with yeast PASK and protein groups Screening and Identification many substrates and show that this kinases participates in regulating carbohydrate metabolism and translation (18).The external phosphorylation glycogen synthetase of the previous yeast PASK of demonstration and the glycogen synthetase of the strain system (PSK1 and PSK2) of disappearance PASK gene be active to raise and compares the 5-10 glycogen accumulation doubly of having an appointment of wild-type strain system, this and the ability impaired consistent (18) of the interior phosphorylation glycogen synthetase of body.Because glycogen is synthetic and translation is the process of the tight adjusting of response nutrient substance operability, and because the PAS structural domain is participated in the metabolism induction usually, proposes the effect of PASK in the cellular response metabolism state.Really, prove that in the recent period Mammals PASK works in the cellular response nutrient substance.The catalytic activity response glucose of PASK in beta Cell of islet adds and increases fast, and some β cytogenes comprise that the glucose responding property expression of preproinsulin needs PASK (23).

Yet the PASK catalytic activity is response glucose not only.Interaction between hPASK region intermediate and the glycogen synthetase is regulated by two kinds of factors at least.The first, the kinase whose PAS structural domain of PAS plays negative interaction in regulating this interaction.If PAS structural domain disappearance or destruction, then hPASK is related with glycogen synthetase more stable.Such as to the proposition of PASK PAS structural domain institute, PAS structural domain function receives the metabolism state of host cell usually and controls (23).This observation has produced interesting possibility: the interaction of hPASK glycogen synthetase receives the adjusting of the metabolism state of said cell, therefore realizes the extra play that the metabolism of glycogen synthetic is regulated.The second, the negative hPASK-of adjusting of glycogen glycogen synthetase interacts, and this is seemingly counterintuitive at first, because glycogen will stimulate himself constantly synthetic like this.Yet should mechanism spatially to coordinate glycogen synthetic thereby possibly exist.Glycogen synthesizes become more and more obviously (30) with highly organized spatial model in cell.A kind of function of hPASK possibly be to keep the inactivation form that free non-localized glycogen synthetase is in phosphorylation to be properly positioned on the already present suitable organized glycogenosome up to it.These data show that effectively the hPASK region intermediate is with the vital role in the hPASK catalytic activity targeted cells internal specific substrate.

Because as if find that in the recent period hPASK relates to the glucose induction and glucose responding property is transcribed, the glucose signals transmission that relies on hPASK influences Glycogen Metabolism in the body.As everyone knows, the Glycogen Metabolism disorder is that 1 type and diabetes B (20) and associated conditions (21) comprise one of characteristics of whole life-threatening cardiovascular disorders (22).Prove further that with the PASK1 mouse PASK is that the normal insulin secretion of pancreatic beta cell is required really, and the PASK disappearance phenotype that causes high fat diet is caused is near resistance completely, said phenotype comprises obesity, insulin resistance and the accumulation of liver fat.Therefore, PASK suppresses to comprise the metabolism system of glucose utilization and storage in the mammalian cell, and provides and treat the novel method that metabolic trouble includes but not limited to mellitus and complication, metabolic syndrome, insulin resistance and various cardiovascular disorders.

The characteristics of cancer, cell transition growth and hyper-proliferative need the synthetic fast of all cells material, comprise albumen and lipid.These building-up processes all receive the control of PASK to a certain extent.Be to suppress the feasible therapeutic strategy that PASK can be used as many cancers through these observable results.Through stoping the synthetic fast of albumen and lipid, this type of suppressor factor stops the quick and uncontrolled growth and the division of the cell that characterizes many cancers.

In compounds disclosed by the invention and the pharmaceutical composition some can suppress PASK, and disclosed the method for synthesizing and use these compounds, comprises through giving the method for the disease of PASK mediation among this compounds for treating patient.

The compound of structural formula I is provided In some embodiments of the present invention:

Or its pharmacy acceptable salt, ester or its prodrug, in the formula:

X ₁And X ₂Be selected from CH and N independently of one another;

R ₁And R ₂Be selected from alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl and NR independently of one another ₅R ₆, wherein any group all can be optionally substituted, and prerequisite is R ₁Or R ₂In at least one is NR ₅R ₆

R ₃Be selected from hydrogen, halogen, trifluoromethyl, hydroxyl, C ₁-C ₅Alkyl and C ₁-C ₅Alkoxyl group, wherein any group all can be optionally substituted;

R ₄Be selected from COOR ₇, NO ₂, CONR ₈R ₉, CONR ₁₀OR ₁₁And tetrazyl;

R ₅And R ₆Be selected from hydrogen, alkyl, naphthenic base, Heterocyclylalkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl independently of one another, wherein any group all can be optionally substituted; Or R ₅And R ₆Can form Heterocyclylalkyl or heteroaryl together, wherein any group all can be optionally substituted;

R ₇, R ₈, R ₉, R ₁₀, and R ₁₁Be selected from hydrogen, C independently of one another ₁-C ₆Alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, wherein any group all can be optionally substituted;

R ₁₈And R ₁₉Be independently selected from naphthenic base, Heterocyclylalkyl, aryl and heteroaryl, wherein any group all can be optionally substituted; And

M and n are the integer of 0-2 independently of one another.

Some compound as herein described has useful PASK regulation activity, can be used for treating or preventing disease or the illness that PASK has a positive effect.Therefore, aspect extensively in, some embodiment also provides the pharmaceutical composition that comprises one or more compounds described herein and pharmaceutically acceptable carrier, and preparation and use said compound and method for compositions.Some embodiment provides the method for regulation and control PASK.Other embodiment provides the method for the disease of treatment PASK mediation in the patient of this treatment of needs, and this method comprises The compounds of this invention or the compsn that gives said patient treatment significant quantity.The purposes of some compound as herein described in medication preparation also is provided, and said medicine is used to treat can be through suppressing disease or the illness that PASK improves.

Or its pharmacy acceptable salt, ester or its prodrug, in the formula:

X ₁And X ₂Be selected from CH and N independently of one another;

R ₅And R ₆Be selected from hydrogen, C independently of one another ₁-C ₆Alkyl, C ₁-C ₇Naphthenic base, C ₁-C ₇Heterocyclylalkyl, C ₁-C ₆Thiazolinyl, C ₁-C ₆Alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl, wherein any group all can be optionally substituted; Or R ₅And R ₆Can form Heterocyclylalkyl or heteroaryl together, wherein any group all can be optionally substituted;

M and n are the integer of 0-2 independently of one another.

The compound of formula I is provided in some embodiments, wherein X ₁And X ₂Be N.

The compound of formula I is provided in some embodiments, wherein R ₄Be COOR ₇

The compound of formula I is provided in some embodiments, wherein

R ₁Be selected from alkyl, phenyl and heteroaryl, and contain one or more substituting groups that are selected from down group: hydrogen, halogen, alkyl, thiazolinyl, alkynyl, naphthenic base, alkylhalide group, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroarylalkyl, CN, alkoxyl group, alkylamino, dialkyl amido, NHSO ₂R ₁₂, NHSO ₂NHR ₁₂, NHCOR ₁₂, NHCONHR ₁₂, CONHR ₁₂, CONR _12aR _12b, hydroxyl and OCF ₃With

R ₁₂, R _12aAnd R _12bBe independently selected from hydrogen, C ₁-C ₆Alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, wherein any group all can be optionally substituted.

The compound of formula I is provided in some embodiments, wherein

R ₂Be selected from phenyl and heteroaryl and have one or more substituting groups that are selected from down group: hydrogen, halogen, alkyl, thiazolinyl, alkynyl, naphthenic base, alkylhalide group, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroarylalkyl, CN, alkoxyl group, alkylamino, dialkyl amido, NHSO ₂R ₁₃, NHSO ₂NHR ₁₃, NHCOR ₁₃, NHCONHR ₁₃, CONHR ₁₃, CONR _13aR _13b, hydroxyl and OCF ₃With

R ₁₃, R _13aAnd R _13bBe independently selected from hydrogen, C ₁-C ₆Alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, wherein any group all can be optionally substituted.

The compound of formula I is provided in some embodiments, wherein R ₁₈And R ₁₉Choose replacement wantonly with one or more substituting groups that are selected from down group: hydrogen, halogen, alkoxyl group, halogenated alkoxy, alkyl and amino.

The compound of formula I is provided in some embodiments, wherein R ₇Be hydrogen.

The compound of formula I is provided in some embodiments, and wherein m is 0.

The compound of formula I is provided in some embodiments, and wherein n is 0.

The compound of structural formula II is provided In some embodiments of the present invention:

(II)

Or its salt, ester or prodrug, in the formula:

R ₂Be selected from alkyl, aryl and heteroaryl, wherein any group all can be chosen wantonly by one or more substituting groups that are selected from down group and replace: hydrogen, halogen, alkyl, thiazolinyl, alkynyl, naphthenic base, alkylhalide group, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroarylalkyl, CN, alkoxyl group, alkylamino, dialkyl amido, NHSO ₂R ₁₃, NHSO ₂NHR ₁₃, NHCOR ₁₃, NHCONHR ₁₃, CONHR ₁₃, CONR _13aR _13b, hydroxyl and OCF ₃With

R ₃Be selected from hydrogen, hydroxyl, C ₁-C ₅Alkyl and C ₁-C ₅Alkoxyl group, wherein any group all can be optionally substituted;

R ₁₄And R ₁₅Be independently selected from hydrogen, C ₁-C ₆Alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, or R ₁₄And R ₁₅Can form Heterocyclylalkyl together, wherein any group all can be optionally substituted; With

The compound of structure formula III is provided In some embodiments of the present invention:

Or its salt, ester or prodrug, in the formula:

R ₂Be selected from alkyl, aryl and heteroaryl, wherein any group all can be chosen wantonly by one or more substituting groups that are selected from down group and replace: hydrogen, halogen, alkyl, thiazolinyl, alkynyl, naphthenic base, alkylhalide group, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroarylalkyl, CN, alkoxyl group, alkylamino, dialkyl amido, NHSO ₂R ₁₃, NHSO ₂NHR ₁₃, NHCOR ₁₃, NHCONHR ₁₃, CONHR ₁₃, CONR _13aR _13b, hydroxyl and OCF ₃

R ₃Be selected from hydrogen and hydroxyl;

R ₁₃, R _13aAnd R _13bBe independently selected from hydrogen, C ₁-C ₆Alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, wherein any group all can be optionally substituted;

R ₁₇Be selected from nothing, hydrogen, alkyl, naphthenic base, Heterocyclylalkyl, aryl and heteroaryl, wherein any group all can be optionally substituted; With

X ₄Be selected from CH, N and O.

The compound of structural formula IV is provided In some embodiments of the present invention:

Or its salt, ester or prodrug, in the formula:

Rz is selected from OH, NR ₈, R ₉, NR ₈OR ₉

R ₁Be selected from aryl and heteroaryl, wherein any group all can be chosen wantonly by one or more substituting groups that are selected from down group and replace: hydrogen, halogen, alkyl, thiazolinyl, alkynyl, naphthenic base, alkylhalide group, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroarylalkyl, CN, alkoxyl group, alkylamino, dialkyl amido, NHSO ₂R ₁₂, NHSO ₂NHR ₁₂, NHCOR ₁₂, NHCONHR ₁₂, CONHR ₁₂, CONR _12aR _12b, hydroxyl, SO ₂R ₁₂, SO ₂NHR ₁₂, CF ₃And OCF ₃

R ₅And R ₆Be independently selected from hydrogen, C ₁-C ₆Alkyl, C ₁-C ₇Naphthenic base, C ₁-C ₇Heterocyclylalkyl, C ₁-C ₆Thiazolinyl, C ₁-C ₆Alkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl, or R ₅And R ₆Can form Heterocyclylalkyl or heteroaryl together, wherein any group all can be optionally substituted;

R ₈And R ₉Be selected from hydrogen, C independently of one another ₁-C ₆Alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, wherein any group all can be optionally substituted; With

R ₁₂, R _12aAnd R _12bBe independently selected from hydrogen, C ₁-C ₆Alkyl, aryl, heteroaryl, aralkyl, CF ₃And heteroaralkyl, wherein any group all can be optionally substituted.

The compound of formula IV is provided in some embodiments, wherein

R ₁For phenyl and have one or more be selected from down the group substituting groups: hydrogen, halogen, alkyl, thiazolinyl, alkynyl, naphthenic base, alkylhalide group, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroarylalkyl, CN, alkoxyl group, alkylamino, dialkyl amido, NHSO ₂R ₁₂, NHSO ₂NHR ₁₂, NHCOR ₁₂, NHCONHR ₁₂, CONHR ₁₂, CONR _12aR _12b, hydroxyl and OCF ₃With

The compound of formula IV is provided in some embodiments, wherein R ₅And R ₆Be C independently ₁-C ₆Alkyl.

The compound of formula IV is provided in some embodiments, wherein R ₃Be hydrogen.

Listed in compound in some embodiments such as the claim 12, R wherein ₅And R ₆Be C independently ₁-C ₆Alkyl.

The compound of structural formula V is provided In some embodiments of the present invention:

Or its salt, ester or prodrug, in the formula:

R ₁Be selected from aryl and heteroaryl, wherein any group all can be chosen wantonly by one or more substituting groups that are selected from down group and replace: hydrogen, halogen, alkyl, thiazolinyl, alkynyl, naphthenic base, alkylhalide group, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroarylalkyl, CN, alkoxyl group, alkylamino, dialkyl amido, NHSO ₂R ₁₂, NHSO ₂NHR ₁₂, NHCOR ₁₂, NHCONHR ₁₂, CONHR ₁₂, CONR _12aR _12b, hydroxyl, CF ₃, SO ₂R ₁₂, NHSO ₂R ₁₂And OCF ₃

R ₃Be selected from hydrogen and hydroxyl;

R ₁₂, R _12aAnd R _12bBe independently selected from hydrogen, C ₁-C ₆Alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, wherein any group all can be optionally substituted;

R ₁₆Be selected from nothing, hydrogen, alkyl, naphthenic base, Heterocyclylalkyl, aryl and heteroaryl, wherein any group all can be optionally substituted;

R ₁₇Be selected from hydrogen and C ₁-C ₆Alkyl; With

X ₃Be selected from CH, N and O.

The compound of structural formula VI is provided In some embodiments of the present invention:

Or its salt, ester or prodrug, in the formula:

Rz is selected from OH, NR ₈, R ₉, NR ₈OR ₉

R ₁Be selected from aryl and heteroaryl, wherein any group all can be chosen wantonly by one or more substituting groups that are selected from down group and replace: hydrogen, halogen, alkyl, thiazolinyl, alkynyl, naphthenic base, alkylhalide group, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroarylalkyl, CN, alkoxyl group, alkylamino, dialkyl amido, NHSO ₂R ₁₂, NHSO ₂NHR ₁₂, NHCOR ₁₂, NHCONHR ₁₂, CONHR ₁₂, CONR _12aR _12b, hydroxyl and CF ₃, SO ₂R ₁₂, SO ₂NHR ₁₂, SO ₂NR _12aR _12b, COOH and OCF ₃

R ₃Be selected from hydrogen and hydroxyl;

R ₈And R ₉Be selected from hydrogen, C independently of one another ₁-C ₆Alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, wherein any group all can be optionally substituted;

R ₁₉Be selected from nothing, hydrogen, alkyl, alkoxyl group, CF ₃, OCF ₃, COOH, halogen, thiazolinyl, alkynyl, hydroxyl, alkyl sulphonyl, cyanic acid, nitro, alkylamino, dialkyl amido, NHSO ₂R ₁₂, NHSO ₂NHR ₁₂, NHCOR ₁₂, NHCONHR ₁₂, CONR _12aR _12b, aryl and heteroaryl;

N is the integer of 0-3;

X ₃Be selected from CH ₂, NR ₁₂, S,, SO ₂And O.

Also provide like the listed compound of claim 1 and be used as medicine.

Also provide like the listed compound of claim 1 to be used for medication preparation, said medicine is used to prevent or treats can be through suppressing disease or the illness that PASK improves.

Compound the purposes in medication preparation listed like claim 9 also is provided, and said medicine is used to prevent or treats can be through suppressing disease or the illness that PASK improves.

The compound that is selected from down group also is provided

2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperazine-1-yl) quinoxaline-6-carboxylic acid,

3-(4-(3-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(4-N-METHYL PIPERAZINE-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

2-phenyl-3-(piperazine-1-yl) quinoxaline-6-carboxylic acid,

2-phenyl-3-(4-phenylpiperazine-1-yl) quinoxaline-6-carboxylic acid,

2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid,

3-(4-(4-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(4-(4-p-methoxy-phenyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(4-(3-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(4-(4-p-methoxy-phenyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

2-phenyl-3-(piperidines-1-yl) quinoxaline-6-carboxylic acid,

2-phenyl-3-(4-Phenylpiperidine-1-yl) quinoxaline-6-carboxylic acid,

3-(azepan-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(4-(4-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-morpholino-2-phenyl quinoxaline-6-carboxylic acid,

3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(isopropylamino)-2-phenyl quinoxaline-6-carboxylic acid,

2-phenyl-3-(4-(pyrimidine-2-base) piperazine-1-yl) quinoxaline-6-carboxylic acid,

2-phenyl-3-(4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid,

2-phenyl-3-(4-(quinoline-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid,

2-(azepan-1-yl)-3-phenyl quinoxaline-6-carboxylic acid,

3-phenyl-2-(piperidines-1-yl) quinoxaline-6-carboxylic acid,

2-(4-(4-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylic acid,

2-(4-(3-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylic acid,

3-(4-fluorophenyl)-2-(4-(4-p-methoxy-phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid,

3-(4-fluorophenyl)-2-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid,

2-phenyl-3-(4-(3-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid,

3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid,

2, two (4-Phenylpiperidine-1-yl) quinoxalines-6-carboxylic acid of 3-,

2, two (4-p-methoxy-phenyl)-6-(1H-tetrazolium-5-yl) quinoxalines of 3-,

3-(4-(N-methylmethane-3-ylsulfonylamino) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(4-(methylsulfonyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(4-(N-methyl kharophen) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(4-(methyl (phenyl) amino) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(diethylamino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(N-methylmethane-5-ylsulfonylamino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(3,4-dihydro-isoquinoline-2 (1H)-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(benzene ethylamino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(methyl (styroyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(hexamethylene is amino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(pipecoline-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(cyclopropyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(second month in a season-butyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

(R)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

(S)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

(R)-3-(2-(methoxymethyl) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

(R)-3-(2-(methylol) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

(S)-3-(2-(methylol) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(3-methylmorpholine generation)-2-phenyl quinoxaline-6-carboxylic acid,

(S)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(4-p-methoxy-phenyl) quinoxaline-6-carboxylic acid,

(R)-3-(methyl (1-phenylethyl) amino)-2-phenyl quinoxaline-6-carboxylic acid.

(S)-3-(methyl (1-phenylethyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

(R)-3-(second month in a season-butyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(1H-indoles-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

2-(3, the 4-difluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(4-chloro-phenyl-)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

(R)-2-phenyl-3-(2-(trifluoromethyl) tetramethyleneimine-1-yl) quinoxaline-6-carboxylic acid,

3-(6-methoxyl group-3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(indoline-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(2; 3-dihydrobenzo [b] [1; 4]

piperazine-4-yl)-2-phenyl quinoxaline-6-carboxylic acid

3-(sec.-propyl (methyl) amino)-2-(3-p-methoxy-phenyl) quinoxaline-6-carboxylic acid,

2-(3-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(2-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(cyclopentyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

(S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(piperidines-1-yl) quinoxaline-6-butyl carboxylate,

3-(azepan-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid,

2-(benzo [d] [1,3] dioxo-5-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(3-(methoxymethyl) piperidines-1-yl) quinoxaline-6-carboxylic acid,

3-(3,3-lupetidine-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(3-methyl piperidine-1-yl) quinoxaline-6-carboxylic acid,

2-(2,3-dihydrobenzo [b] [1,4] dioxine-6-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(4-(methylsulfonyl) phenyl) quinoxaline-6-carboxylic acid,

2-(benzo [d] [1,3] dioxo-5-yl)-3-((S)-2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylic acid,

2-(1H-indoles-5-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(4-(trifluoromethoxy) phenyl) quinoxaline-6-carboxylic acid,

2-(4-cyano-phenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(pyridin-4-yl) quinoxaline-6-carboxylic acid,

2-(H-imidazoles [1,2-a] pyridine-6-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(cumarone-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

(S)-2-(4-fluorophenyl)-3-(2-methyl-4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid,

(S)-2-(4-fluorophenyl)-3-(pipecoline-1-yl) quinoxaline-6-carboxylic acid,

3-(cyclopropyl (methyl) amino)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid,

(R)-2-(4-fluorophenyl)-3-(2-(methoxymethyl) tetramethyleneimine-1-yl) quinoxaline-6-carboxylic acid,

(S)-3-(2-methyl-4-(pyridine-2-yl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

2-(benzo [d] [1,3] dioxo-5-yl)-3-(3,4-EEDQ-1 (2H)-yl) quinoxaline-6-carboxylic acid,

3-(octahydro quinoline-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(pyridin-3-yl) quinoxaline-6-carboxylic acid,

2-(furans-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(quinoline-3-yl) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(4-morpholino phenyl) quinoxaline-6-carboxylic acid,

3-(1,1-diepoxy thio-morpholinyl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid,

3-(1,1-diepoxy thio-morpholinyl)-2-phenyl quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(3-oxo piperazine-1-yl) quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(methyl (piperidin-4-yl) amino) quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(methyl (tetrahydrochysene-2H-pyrans-4-yl) amino) quinoxaline-6-carboxylic acid,

3-(cyclopentyl (methyl) amino)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(5-thiotolene-2-yl) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(thiophene-2-yl) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(6-methoxypyridine-3-yl) quinoxaline-6-carboxylic acid,

2-(furans-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(4-(N-methyl kharophen) piperidines-1-yl) quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(4-methyl-3-oxo piperazine-1-yl) quinoxaline-6-carboxylic acid,

3-(4-kharophen piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

2-phenyl-3-(2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) quinoxaline-6-carboxylic acid,

(S)-3-(second month in a season-butyl (methyl) amino)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid,

3-(second month in a season-butyl (methyl) amino)-2-(furans-3-yl) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(1H-pyrazoles-4-yl) quinoxaline-6-carboxylic acid,

2-(1H-indazole-6-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(1-methyl isophthalic acid H-indazole-6-yl) quinoxaline-6-carboxylic acid,

2-(1H-indoles-6-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(1-(tert-butoxycarbonyl)-1H-indoles-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(1H-indoles-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(1-(tert-butoxycarbonyl)-5-methoxyl group-1H-indoles-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(5-methoxyl group-1H-indoles-2-yl) quinoxaline-6-carboxylic acid,

2-(5-fluoro-1H-indoles-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(5-bromopyridine-3-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(1H-indazole-5-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(3-(trifluoromethyl)-1H-pyrazoles-4-yl) quinoxaline-6-carboxylic acid,

2-(6-(tert-butoxycarbonyl is amino) pyridin-3-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(5-fluorine pyridine-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(5-(trifluoromethyl) pyridine-2-yl) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(6-(trifluoromethyl) pyridin-3-yl) quinoxaline-6-carboxylic acid,

2-(5-cyanopyridine-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(6-(tetramethyleneimine-1-yl) pyridin-3-yl) quinoxaline-6-carboxylic acid,

2-(6-fluorine pyridin-3-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

(S)-2-(cumarone-2-yl)-3-(2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylic acid,

2-(cumarone-2-yl)-3-(cyclopropyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(5-fluorobenzene and furans-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(5-chlorobenzene and furans-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid and

2-(cumarone-2-yl)-3-(second month in a season-butyl (methyl) amino) quinoxaline-6-carboxylic acid.

The pharmaceutical composition that comprises above-claimed cpd and pharmaceutically acceptable carrier also is provided.

The method that suppresses PASK also is provided, and said method comprises PASK is contacted with above-claimed cpd.

The method of treatment disease also is provided, and said method comprises that the above-claimed cpd with the treatment significant quantity needs its patient.

Aforesaid method also is provided, and wherein said disease is selected from cancer and metabolic trouble.

Aforesaid method also is provided, and wherein said disease is a metabolic trouble.

Aforesaid method also is provided, and wherein said metabolic trouble is selected from metabolic syndrome, mellitus, dyslipidemia, fatty liver disease, nonalcoholic fatty liver disease, obesity and insulin resistance.

Aforesaid method also is provided, and wherein said mellitus are type ii diabetes.

Aforesaid method also is provided, and wherein said dyslipidemia is a hyperlipidaemia.

Also be provided at the method that realizes effect among the patient, said method comprises that the above-claimed cpd with the treatment significant quantity gives the patient, and wherein said effect is selected from down group: triglyceride level reduces, SUV reduces and HbA1 c reduces.

Aforesaid method also is provided, and wherein said SUV is selected from LDL and VLDL SUV.

Aforesaid method also is provided, and wherein said triglyceride level is selected from plasma triglyceride and liver triglyceride level.

The method of the disease of treatment PASK mediation also is provided, and said method comprises and giving:

A. treat the above-claimed cpd of significant quantity; With

B. another kind of therapeutical agent.

Be not limited to any theory or the mechanism of action; The disclosed compound of this paper can be used for treatment or regulation and control metabolic trouble (include but not limited to mellitus, metabolic disturbance, dyslipidemia, fatty liver disease, nonalcoholic fatty liver disease, obesity and insulin resistance, and be used for triglyceride reducing, SUV and HbA1 c) and cancer.

Description of drawings

Supporting agent in the research in Fig. 1 display body-, WAY-and through the rat of motif compound treatment changes of weight along with the time.

As used among this paper, following term has following implication.

If disclosed numerical range and used label " from n _1......To n ₂", n wherein ₁And n ₂Be numeral, except as otherwise noted, this label is intended to comprise numerical value itself and scope therebetween.This scope can be integer or between end value continuously and comprise end value.For example, scope " from 2 to 6 carbon " means and comprises 2,3,4,5 and 6 carbon, because carbon is graduation of whole numbers of units.Comparatively speaking, for example, scope " from 1 to 3 μ M (micromole) " means and comprises 1 μ M, 3 μ M and all any significant figure (for example, 1.255 μ M, 2.1 μ M, 2.9999 μ M etc.) therebetween.

The term " about " of using among this paper is intended to the quantitatively numerical value of its modification, and indicating this value is the variable in certain error margin.If average given in the data drawing list is not quoted concrete error margin, standard deviation for example, term " about " are interpreted as representing to contain this value of quoting and consider the scope that significant figure comprise through operation that this numeral is rounded off.

Term used herein " acyl group " when being used alone or in combination, refers to be connected in thiazolinyl, alkyl, aryl, naphthenic base, heteroaryl, heterocycle, or the atom that is connected on the carbonyl is the carbonyl of any other part of carbon." ethanoyl " refers to-C (O) CH ₃Group." alkyl-carbonyl " or " alkyloyl " refers to be connected in through carbonyl the alkyl of parent molecular moiety.The example of this type group comprises methyl carbonyl and ethyl carbonyl.The example of acyl group comprises formyl radical, alkyloyl and aroyl.

Term used herein " thiazolinyl " when being used alone or in combination, refers to the straight or branched hydrocarbyl group that has one or more pairs of keys and comprise from 2 to 20 carbon atoms.In some embodiments, said thiazolinyl comprises 2-6 carbon atom.Term " alkenylene " refers to the carbon-to-carbon double bond system that connects in two or more positions, like vinylidene [(CH=CH-), (C::C-)].The example of suitable thiazolinyl comprises vinyl, propenyl, 2-methylpropenyl, 1,4-butadienyl etc.Except as otherwise noted, term " thiazolinyl " can comprise " alkenylene ".

Term used herein " alkoxyl group " when being used alone or in combination, refers to alkyl ether groups, and wherein term alkyl is following defines.The example of suitable alkyl ether groups comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, tert.-butoxy etc.

Term used herein " alkyl " when being used alone or in combination, refers to contain the straight or branched alkyl of 1 to 20 carbon atom.In some embodiments, said alkyl will comprise 1 to 10 carbon atom.In other embodiments, said alkyl will comprise 1-6 carbon atom.Alkyl can be like defined herein being optionally substituted.The example of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec.-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, octyl group, nonyl etc.Term used herein " alkylidene group " when being used alone or in combination, refers to the saturated fatty base derived from the straight or branched stable hydrocarbon that connects in two or more sites, like methylene radical (CH ₂-).Except as otherwise noted, term " alkyl " can comprise " alkylidene group ".

Term used herein " alkylamino " when being used alone or in combination, refers to be connected to through amino group the alkyl group of parent molecular moiety.Suitable alkylamino can be that monoalkyl or dialkyl group are substituted, forms such as N-methylamino, N-ethylamino, N, N-dimethylamino, N, groups such as N-ethylmethylamino.

Term used herein " alkylidene " when being used alone or in combination, refers to alkenyl group, and wherein carbon-carbon double bond carbon atom belongs to the part that connects alkenyl group.

Term used herein " alkylthio " when being used alone or in combination, refer to alkylthio ether (R-S-) group, but wherein term alkyl defines as above and wherein sulphur unit price or divalence oxidation.The example of suitable alkylthio ether group comprise methylthio group, ethylmercapto group, just-rosickyite base, iprotiazem base, just-butylthio, isobutyl sulfenyl, secondary butylthio, uncle's butylthio, methylsulfonyl, second sulfinyl etc.

Term used herein " alkynyl " when being used alone or in combination, refers to the straight or branched hydrocarbyl group that has one or more triple bonds and contain 2 to 20 carbon atoms.In some embodiments, said alkynyl comprises 2 to 6 carbon atoms.In other embodiments, said alkynyl comprises 2 to 4 carbon atoms.Term " alkynylene " refers to the carbon-to-carbon triple bond two sites connections, such as ethynylene (C:::C-,-C ≡ C-).The example of alkynyl group comprises ethynyl, proyl, hydroxypropyn base, butine-1-base, crotonylene-Ji, pentyne-1-base, 3-methyl butine-1-base, hexin-2-base etc.Only if point out in addition, term " alkynyl " can comprise " alkynylene " group.

Term used herein " amido " and " carbamyl " when being used alone or in combination, refer to following describedly be connected in the amino group on the parent molecular moiety through carbonyl group, and vice versa.Term used herein " C-amido ", when being used alone or in combination, refer to-C (=O)-NR ₂Group, wherein the definition of R is as described herein.Term used herein " N-amido " when being used alone or in combination, refers to RC (=O) NH-group, and R such as defined herein.Term used herein " acyl amino " when being used alone or in combination, comprises through amino being connected in the acyl group on the parent fraction.The example of " acyl amino " group is acetylamino (CH ₃C (O) NH-).

Term used herein " amino " when being used alone or in combination, refers to-NRR ', and wherein R and R ' are independently selected from hydrogen, alkyl, acyl group, assorted alkyl, aryl, naphthenic base, heteroaryl and Heterocyclylalkyl, and wherein any group self all can be optionally substituted.In addition, R and R ' formation Heterocyclylalkyl capable of being combined, wherein any group all can be optionally substituted.

Term used herein " aryl " when being used alone or in combination, refers to contain the carbocyclic ring aroma system of one, two or three ring, and wherein this multi-loop system condenses together.Term " aryl " comprises such as aryl such as phenyl, naphthyl, anthryl and phenanthryl.

Term used herein " aryl alkenyl " or " arylalkenyl " when being used alone or in combination, refer to be connected to the aromatic yl group on the parent molecular moiety through alkenyl group.

Term used herein " alkoxy aryl " or " aralkoxy " when being used alone or in combination, refer to be connected to the aromatic yl group on the parent molecular moiety through alkoxy base.

Term used herein " arylalkyl " or " aralkyl " when being used alone or in combination, refer to be connected to the aromatic yl group on the parent molecular moiety through alkyl group.

Term used herein " aromatic yl polysulfide yl " or " sweet-smelling alkynyl " when being used alone or in combination, refer to be connected to the aromatic yl group on the parent molecular moiety through alkynyl group.

Term used herein " aromatic yl silane terephthalamide yl " or " aralkanoyl " or " aroyl "; When being used alone or in combination, refer to derived from the carboxyl groups of the alkyl carboxylic acid of acyl substituted such as benzoyl-, naphthoyl base, phenyl acetyl, 3-phenyl propionyl group (hydrocinnamoyl), 4-phenyl butyryl radicals, (2-naphthyl) ethanoyl, 4-chlorine hydrocinnamoyl etc.

Term aryloxy used herein when being used alone or in combination, refers to that logical peroxy is connected to the aromatic yl group of parent molecular moiety.

Term used herein " benzo " and " benzene-" when being used alone or in combination, refer to the divalent group C derived from benzene ₆H ₄=.Example comprises thionaphthene and benzoglyoxaline.

Term used herein " carbamate " when being used alone or in combination, refers to that (ester NHCOO-), it can and can be optionally substituted as defined herein from the terminal or sour terminal connection parent molecular moiety of nitrogen carboxylamine.

Term used herein " O-carbamyl " when being used alone or in combination, refers to-OC (O) NRR ' group, and wherein the definition of R and R ' is as described herein.

Term used herein " N-carbamyl " when being used alone or in combination, refers to ROC (O) NR '-group, and wherein the definition of R and R ' is as described herein.

Term used herein " carbonyl " comprises formyl radical [C (O) H] when using separately, and combination when using is-C (O)-group.

Term used herein " carboxyl " or " carboxylic " refer to-C (O) OH or corresponding " carboxylate radical " negatively charged ion, such as in carboxylate salt." O-carboxyl " refers to RC (O) O-group, and wherein the definition of R is as described herein." C-carboxyl " refers to-C (O) OR group, and wherein the definition of R is as described herein.

Term used herein " cyanic acid " when being used alone or in combination, refers to-CN.

Term used herein " naphthenic base " is " carbocyclic ring " perhaps; When being used alone or in combination; The monocycle, dicyclo or the tricyclic alkyl that refer to saturated or fractional saturation; Wherein each loop section contains 3-12 carboatomic ring member, and the benzo-fused loop systems that can randomly be optionally substituted for the definition like this paper.In some embodiments, said naphthenic base comprises 3-7 carbon atom.The example of this type naphthenic base comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, tetralyl, indanyl, octahydro naphthyl, 2,3-dihydro-1H-indenyl, adamantyl etc.Term used herein " dicyclo " and " three ring " are intended to comprise the fused rings system such as naphthane, octalin and polycyclic (polycentric) are saturated or the unsaturated type of part.Isomer back one type normally, for example, dicyclo [1,1,1] pentane, camphor, diamantane and dicyclo [3,2,1] octane.

Term used herein " ester " when being used alone or in combination, refers to the carboxyl of two parts of bridge joint on carbon atom.

Term used herein " ether " when being used alone or in combination, refers to the oxygen base in two parts of carbon atom bridge joint.

Term used herein " halogen " or " halogen " when being used alone or in combination, refer to fluorine, chlorine, bromine or iodine.

Term used herein " halogenated alkoxy " when being used alone or in combination, refers to be connected to the haloalkyl on the parent molecular moiety through Sauerstoffatom.

Term used herein " haloalkyl " when being used alone or in combination, refers to have the as above alkyl group of defined implication, and wherein one or more hydrogen are replaced by halogen.Comprise single haloalkyl, dihalo alkyl and multi-haloalkyl group especially.For example, single haloalkyl can contain iodine atom, bromine atoms, chlorine atom or fluorine atom in group.Dihalo alkyl and multi-haloalkyl can contain the combination of two or more identical halogen atoms or different halogen group.The example of haloalkyl comprises methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl group, seven fluoropropyls, difluoro chloromethyl, dichlorofluoromethyl, two fluoro ethyls, two fluoropropyls, Dichloroethyl and two chloropropyls." halo alkylidene group " refers to the haloalkyl that on two or more positions, connects.Example comprises fluoro methylene radical (CFH-), difluoro methylene (CF ₂-), the chloro methylene radical (CHCl-) etc.

Term used herein " assorted alkyl "; When being used alone or in combination; Refer to stable straight or branched hydrocarbyl group or their combination, fully saturated or have 1 to 3 degree of unsaturation, form by the carbon atom and one to three heteroatoms that is selected from O, N and S of defined number; And nitrogen-atoms wherein and sulphur atom can be randomly oxidized, and nitrogen heteroatom can randomly be substituted or quaternized.Heteroatoms O, N and S can be positioned on any interior location of assorted alkyl.2 successive heteroatomss can appear at the most, for example-and CH ₂-NH-OCH ₃

Term used herein " heteroaryl " when being used alone or in combination, referring to 3 to 7 yuan of unsaturated assorted monocycles, or condenses monocycle, dicyclo or three-loop system, and wherein at least one of fused rings is aromatic nucleus, comprises the atom that at least one selects white O, S and N.In some embodiments, said heteroaryl comprises 5-7 carbon atom.This term also comprises the many cyclic groups of condensed interior, and wherein heterocycle and aromatic nucleus condense, and wherein heteroaryl ring and other heteroaryl rings condense, and wherein heteroaryl ring and heterocycloalkyl ring condense, or wherein heteroaryl ring and cycloalkyl ring condense.The example of heteroaryl comprises pyrryl; Pyrrolinyl; Imidazolyl; Pyrazolyl; Pyridyl; Pyrimidyl; Pyrazinyl; Pyridazinyl; Triazolyl; Pyranyl; Furyl; Thienyl;

azoles base; Different

azoles base;

di azoly; Thiazolyl; Thiadiazolyl group; Isothiazolyl; Indyl; Pseudoindoyl; The pyrrocoline base; Benzimidazolyl-; Quinolyl; Isoquinolyl; Quinoxalinyl; Quinazolyl; Indazolyl; The benzotriazole base; The benzo dioxolyl; Benzopyranyl; Benzo azoles base; Benzo

di azoly; Benzothiazolyl; The diazosulfide base; Benzofuryl; Benzothienyl; The chromone base; Coumaric acyl (coumarinyl); Benzopyranyl; Tetrahydric quinoline group; The tetrazolo pyridazinyl; Tetrahydro isoquinolyl; The thienopyridine base; The furo pyridyl; Pyrrolopyridinyl etc.The example of tricyclic heterocyclic base comprises carbazyl, benzindole base, phenanthroline base, dibenzofuran group, acridyl, phenanthridinyl, xanthenyl etc.

Term used herein " Heterocyclylalkyl " and interchangeable terms " heterocycle "; When being used alone or in combination; Refer to separately saturated, part is undersaturated or undersaturated monocycle, dicyclo or the tricyclic heterocyclic group that contains at least one heteroatoms as ring members fully, wherein each described heteroatoms can be independently selected from nitrogen, oxygen and sulphur.In certain embodiments, said Heterocyclylalkyl will comprise 1 to 4 heteroatoms as ring members.In other embodiments, said Heterocyclylalkyl will comprise 1 to 2 heteroatoms as ring members.In certain embodiments, said Heterocyclylalkyl will comprise 3 to 8 ring memberses in each ring.In other embodiments, said Heterocyclylalkyl will comprise 3 to 7 ring memberses in each ring.In other embodiments, said Heterocyclylalkyl will comprise 5 to 6 ring memberses in each ring." Heterocyclylalkyl " and " heterocycle " is intended to comprise sulfone, sulfoxide, uncle's azo-cycle member's N-oxide compound and carbocyclic fused and benzo-fused loop systems; In addition, these two terms comprise that also the aromatic group of heterocycle and this paper definition condenses, or with other heterocyclic group condensed system.The example of heterocyclic group comprises '-aziridino, azetidine base, 1; 3-benzo dioxolyl, dihydro-iso indolyl, dihydro-isoquinoline base, dihydro cinnolines base, dihydrobenzo two Ying Ji, dihydro [1; 3]

azoles also [4; 5-b] pyridyl, benzothiazolyl, indolinyl, dihydropyridine base, 1; 3-two

alkyl, 1; 4-two

alkyl, 1; 3-dioxolanyl, iso-dihydro-indole-group, morpholinyl, piperazinyl, pyrrolidyl, tetrahydro pyridyl, piperidyl, thio-morpholinyl, 3,4-methylenedioxyphenyl etc.Only if forbid especially, heterocyclic group can be optional substituted.

Term used herein " diazanyl " when being used alone or in combination, refers to connected promptly by singly-bound-N-N-and be not included in 2 amino groups of intra-annular.

Term used herein " hydroxyl " when being used alone or in combination, refers to-OH.

Term used herein " hydroxyalkyl " when being used alone or in combination, refers to be connected to the oh group on the parent molecular moiety through alkyl group.

Term used herein " imino-" when being used alone or in combination, refers to=N-.

Term used herein " imino-hydroxyl ", when being used alone or in combination, refer to=N (OH) and=N-O-.

Phrase " on main chain " refers to originate in the longest the adjoining or contiguous chain of carbon atom of tie point of the compound of group and any formula disclosed herein.

Term " isocyanato " refers to-the NCO group.

Term " isothiocyanic acid base " refers to-the NCS group.

Phrase " linear atomchain " refers to independently to be selected from the long linear of the atom of carbon, nitrogen, oxygen and sulphur.

Term used herein " rudimentary ", when being used alone or in combination, only if special in addition the qualification, the meaning is to contain individual carbon atom 1 to 6 (containing 6).

Term used herein " lower aryl ", when being used alone or in combination, the expression phenyl or naphthyl, it can be optionally substituted as said.

Term used herein " rudimentary heteroaryl ", when being used alone or in combination, expression 1) contain the bicyclic heteroaryl of 5 or 6 ring memberses, wherein 1-4 said member can be the heteroatoms that is selected from O, S and N; Or 2) bicyclic heteroaryl, wherein each condensed ring comprises 5 or 6 ring memberses, and wherein 1-4 said member can be the heteroatoms that is selected from O, S and N.

Term used herein " low-grade cycloalkyl ", when being used alone or in combination, expression has the monocyclic cycloalkyl of 3-6 ring members.Low-grade cycloalkyl can be undersaturated.The example of low-grade cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Term used herein " rudimentary Heterocyclylalkyl ", when being used alone or in combination, expression has the monocyclic heterocycles alkyl of 3-6 ring members, and wherein 1-4 said member can be the heteroatoms that is selected from O, S and N.The example of rudimentary Heterocyclylalkyl comprises pyrrolidyl, imidazolidyl, pyrazolidyl, piperidyl, piperazinyl and morpholinyl.Rudimentary Heterocyclylalkyl can be undersaturated.

Term used herein " rudimentary amino " when being used alone or in combination, refers to-NRR ', and wherein R and R ' are independently selected from hydrogen, low alkyl group and rudimentary assorted alkyl, and wherein any group all can be optionally substituted.In addition, the R of rudimentary amino group and R ' formation 5 capable of being combined or 6 yuan of Heterocyclylalkyls, wherein any group all can be optionally substituted.

Term used herein " sulfydryl " when being used alone or in combination, refers to the RS-group, wherein R such as defined herein.

Term used herein " nitro " when being used alone or in combination, refers to-NO ₂

Term used herein " oxygen " or " oxa-" when being used alone or in combination, refer to-O-.

Term used herein " oxo " when being used alone or in combination, refers to=O.

Term used herein " perhalogeno alkoxyl group " refers to that all Wasserstoffatomss are all by the substituted alkoxy base of halogen atom.

Term used herein " perhaloalkyl radical " when being used alone or in combination, refers to that all Wasserstoffatomss are all by the substituted alkyl group of halogen atom.

Term used herein " sulphonate ", " sulfonic acid " and " sulfonic group " when being used alone or in combination, refer to when sulfonic acid is used as salt form-SO ₃H group and its negatively charged ion.

Term used herein " sulfane base " when being used alone or in combination, refers to-S-.

Term used herein " sulfinyl ", when being used alone or in combination, refer to-S (O)-.

Term used herein " alkylsulfonyl " when being used alone or in combination, refers to-S (O) ₂-.

Term used herein " N-sulfonamido " refer to RS (=O) ₂NR '-group, wherein R and R ' are as defined herein.

Term used herein " S-sulfonamido " refer to-S (=O) ₂NRR ' group, wherein R and R ' are as defined herein.

Term used herein " thiophene " and " sulfo-", when being used alone or in combination, refer to-S-group or oxygen wherein is by the substituted ether of sulphur.The oxidized derivatives of thio group, promptly sulfinyl and alkylsulfonyl also are comprised among the definition of thiophene and sulfo-.

Term used herein " mercaptan " when being used alone or in combination, refers to-the SH group.

Term used herein " thiocarbonyl " comprises thioformyl-C (S) H when using separately, combination when using is-C (S)-group.

Term " N-thiocarbamoyl " refers to ROC (S) NR '-group, and wherein R and R ' are as defined herein.

Term " O-thiocarbamoyl " refers to-OC (S) NRR ' group, and wherein R and R ' are as defined herein.

Term " thiocyano " refers to-the CNS group.

Term " three halogen methoxyl groups " refers to X ₃The CO-group, wherein X is a halogen.

Any definition of this paper can be used to describe a kind of composite structure group with other any combinations of definitions.Traditionally, the suffix composition of any such definition refers to be connected on the parent fraction.For example, compound group alkyl amido can be represented the alkyl group that is connected with parent molecule through amido, and term alkoxy alkyl can be represented the alkoxy base that is connected with parent molecule through alkyl group.

When a group is defined as " nothing ", the meaning is that described group does not exist.

Term " the optional replacement " means previous group and can be substituted or not be substituted.When being substituted, the substituting group of " optional replace " group can include but not limited to one or more be independently selected from a following group or a specially appointed group set, substituting group alone or in combination: low alkyl group, low-grade alkenyl, low-grade alkynyl, low-grade alkane acidyl, rudimentary assorted alkyl, rudimentary Heterocyclylalkyl, low-grade halogenated alkyl, lower halogenated thiazolinyl, lower halogenated alkynyl, rudimentary whole haloalkyl, rudimentary perhalogeno alkoxyl group, low-grade cycloalkyl, phenyl, aryl, aralkyl, aryloxy, lower alkoxy, elementary halogenated alkoxy, oxo, low-grade acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, rudimentary carboxyl ester, rudimentary carboxamido, cyanic acid, hydrogen, halogen, hydroxyl, amino, low-grade alkyl amino, arylamino, amido, nitro, sulfydryl, lower alkylthio, lower halogenated alkylthio, rudimentary perhalogeno alkylthio, arylthio, sulphonate, sulfonic acid, trisubstituted silyl, N ₃, SH, SCH ₃, C (O) CH ₃, CO ₂CH ₃, CO ₂H, pyridyl, thiophene, furyl, rudimentary carbamate and rudimentary urea.Two substituting groups can be joined together to form five yuan of condensed, hexa-atomic or seven-element carbon ring or by 0 to 3 heterocycle that heteroatoms is formed, for example form methylene radical dioxy base or ethylidene dioxy base.Optional substituted group can be not substituted (like-CH ₂CH ₃), substituted fully (like-CF ₂CF ₃), mono-substituted (like-CH ₂CH ₂F) or with replace fully and between single the replacement any level substituted (like-CH ₂CF ₃).Listed substituting group is when replacing indefinite, and substituted and not substituted two kinds of forms are all included.When a substituting group was restricted to " substituted ", then this substituted form was refered in particular in explanation.In addition, the optional substituent different sets of a specific part can define as required; In these cases, optional replacement is directly followed phrase usually and is defined as " quilt ... the optional replacement ".

Term R or R ', only if in addition definition occurs alone and when not having the designation number word, refers to be selected from the part of hydrogen, alkyl, naphthenic base, assorted alkyl, aryl, heteroaryl and Heterocyclylalkyl, wherein any group all can randomly be replaced.Such R and R ' group are construed as being optionally substituted like this paper definition.No matter whether the R group has specified numeral, and each R group comprises R, R ' and R ⁿ(wherein n=(1,2,3 ... n)), each substituting group and each term should be thought separate on group is selected.Any variable, substituting group or term (like aryl, heterocycle, R etc.) occur in a formula or generic structure when once above, the definition the when definition when it occurs at every turn all is independent of other and occurs at every turn.Those skilled in the art will further be familiar with, and some group can be connected with parent molecule or can occupy a position in the element chain at arbitrary end of writing.Therefore, only make usefulness for example, asymmetric group is like-C (O) N (R)-can be connected with parent fraction at carbon or nitrogen place.

There is asymmetric center in the compound described herein.Chiral carbon atom substituent configuration is on every side depended on symbol " R " or " S " expression in these centers.Should be understood that the present invention contained all stereochemistry heterogeneous forms, comprise diastereo-isomerism, enantiomerism and epimerization form, and D-isomer and L-isomer and their mixture.The various steric isomers of compound can be separated by the synthetic mixture for preparing or prepare the enantiomer product of the marketable material that comprises chiral centre then; The mixture that for example is converted into diastereomer separates or recrystallization then; Adopt chromatographic technique; Direct separation enantiomer on chiral chromatographic column perhaps adopts any other suitable method well known by persons skilled in the art.Specific stereochemical starting compound is commercially available to be got or can and differentiate through technology preparation known in the art.In addition, compound described herein can the geometrical isomer form exist.The present invention includes all cis, trans, suitable, anti-, heteropleural (E) and homonymy (Z) isomer and their suitable mixture.In addition, the form that compound can tautomer exists; All tautomers are provided by the present invention.In addition, compound described herein can the non-solvent form and is existed with the form of acceptable solvent such as water, ethanol equal solventization pharmaceutically.It has been generally acknowledged that the solvation form is equal to the non-solvent form.

Covalently bound key between two atoms of term " key " expression if the atom that key is connected is regarded the part of bigger minor structure as, is then represented the covalently bound key between two parts.Except as otherwise noted, key can be singly-bound, two key or triple bond.Two interatomic dotted lines are illustrated in this position and can have or not exist extra key in Molecular Graphs.

Term used herein " disease " and term " imbalance " and roughly synonym and interchangeable use of " illness " (being in the medical condition) are because they all reflect the infringement normal function, show and cause the ERST of one of human or animal body or its part of human or animal's the lost of life or quality of life reduction through S&S usually.

Term " conjoint therapy " expression gives two kinds or more kinds of therapeutical agent to treat illness of the present invention or disease.This administering mode comprises that these therapeutical agents give basically simultaneously, for example in the single capsule of the activeconstituents with fixed ratio, perhaps in a plurality of independent capsule of every kind of activeconstituents, gives jointly.In addition, this administering mode also comprises with sequential system and uses various types of therapeutical agents.Which kind of situation no matter, regimen will provide the beneficial effect of drug regimen in treatment illness described herein or imbalance.

" PASK suppressor factor " used herein refers to the (IC that relative PASK activity shows ₅₀/ EC ₅₀) do not exceed about 100 μ M and more generally do not exceed the compound of about 50 μ M, survey in the following general described PASK experiment.IC ₅₀It is the inhibitor concentration that the PASK activity is reduced to half place of maximum horizontal.Some compound described herein shows inhibition to PASK.

Phrase " treatment effectively " is intended to be limited to the amount of employed activeconstituents in disease or the imbalance treatment.This amount will reach the purpose that alleviates or eliminate described disease or imbalance.

Term " acceptable in the treatment " expression is applicable to and contacts with patient tissue and do not have over-drastic toxicity, pungency and an allergic compound (or salt, prodrug, tautomer, zwitterionic form etc.); With rational benefit/risk than corresponding, and be effective for its specified purposes.

As used herein, " treatment " patient is intended to comprise prevention.Term " patient " refers to all Mammalss, comprises the people.Patient's example comprises people, ox, dog, cat, goat, sheep, pig and rabbit.Preferably, said patient is the people.

Term " prodrug " refers to have more in vivo active compound.Some compound disclosed herein can be used as prodrug and exists; Like Hydrolysis in Drug and Prodrug Metabolism:Chemistry, Biochemistry, and Enzymology (hydrolysis in medicine and the prodrug metabolism: chemistry, biological chemistry and zymetology) (Testa; Bernard and Mayer; Joachim M.Wiley-VHCA, Zurich, SUI, 2003) described in.The prodrug of compound described herein is easily experience chemically changed and the structural modification form of this compound of this compound is provided under physiological conditions.In addition, prodrug can be converted into this compound through chemistry or biochemical method under the environment that exsomatizes.For example, prodrug is placed in skin absorption adhesive patch holder with suitable enzyme or chemical reagent and can slowly be converted into compound.Often use prodrug, because in some cases, they are than this compound or parent drug administration more easily.For example, they possibly utilized by living organism during oral administration, and parent drug can not.Compare with parent drug, the solubleness that prodrug also maybe be in pharmaceutical composition is higher.Various prodrug derivant known in the art for example relies on hydrolysis cutting or oxidation activated prodrug.A nonrestrictive example of prodrug can be a kind of as ester (" prodrug ") give but then metabolism be hydrolyzed to the compound of active entity carboxylic acid.Other examples comprise the peptide radical derivative of compound.

Compound as herein described can be the form that acceptable salt is gone up in treatment.The present invention includes the salt form of above-claimed cpd, comprise acid salt.Suitable salt comprises the salt that forms with organic acid and mineral acid.This type acid salt is normally pharmaceutically acceptable.Yet non-pharmacy acceptable salt can be used for preparing the compound of studying with purifying.Also can form pharmaceutically acceptable base addition salt.For the preparation of salt and the more complete discussion of selection, referring to Pharmaceutical salts:Properties, Selection; And Use (pharmaceutical salts: character, selection and purposes) (Stahl; P.Heinrich.Wi ley-VCHA, Zurich, SUI, 2002).

The salt or the zwitterionic form of term used herein " acceptable salt in the treatment " representative compound disclosed herein as defined herein, are water-soluble or oil soluble or dispersible, and are that treatment is gone up acceptable.This salt can prepare in the final separation of compound and purge process, or through with suitable compound with free alkali form preparation separately with suitable acid-respons.

Though the form that compound of the present invention can original chemical gives, they also can be the forms of pharmaceutical prepn.Therefore; The invention provides pharmaceutical prepn; It comprises one or more some compounds as herein described or its one or more pharmacy acceptable salts, ester, prodrug, acid amides or solvate, and one or more pharmaceutically acceptable carriers and one or more optional other therapeutic components.Said carrier must be " acceptable ", this means that other composition of it and said preparation is compatible, and harmless to the recipient.Proper formula depends on selected route of administration.Can use suitable any technique known, carrier and the vehicle of understanding with this area, for example " Lei Mingdeng pharmaceutical science " (Remington ' s Pharmaceutical Sciences) described in.Pharmaceutical composition of the present invention can any-mode manufacturing known in the art, as, mixing, dissolving, granulation, the agent of manufacturing sugar-coat, the water through routine flies, emulsification, encapsulate, the method for sealing or suppressing.

Preparation comprise be applicable to oral, parenteral (comprise subcutaneous, intracutaneous, intramuscular; In the intravenously, intraarticular and marrow), intraperitoneal; Through mucous membrane; Transdermal, the compsn of rectum and external application (comprise skin, contain clothes, hypogloeeis and intraocular) administration is though only approach possibly depend on for example recipient's state and disease.Said preparation can be a unit dosage easily, any method manufacturing that can know through pharmaceutical field.Usually, these methods may further comprise the steps: compound of the present invention or its pharmacy acceptable salt, ester, acid amides, prodrug or solvate (" activeconstituents ") are combined with the carrier that constitutes one or more ancillary components.Usually, make activeconstituents and liquid vehicle or fine powder solid carrier or the two homogeneous and combine nearly then, if desired,, to obtain required preparation this product moulding with the preparation preparation.

The preparation that is applicable to the compound of oral administration described herein can be the form of the individual of the various activeconstituentss that contain predetermined amount, for example capsule, cachet or tablet; Powder or particle; Solution that in waterborne liquid or non-aqueous liquid, forms or suspension; Or O/w emulsion agent or water in oil emulsion liquor.This activeconstituents also can be made into bolus, electuary or paste.

The other medicines preparation that taking orally is used comprises crimping (push-fit) capsule that tablet, gelatin are processed, and the sealing soft capsule processed of gelatin and softening agent such as glycerine or Sorbitol Powder.Tablet can be through suppressing with one or more optional auxiliary compositions or moulding is made.The making method of compressed tablets can be in suitable machine, the optional activeconstituents such as free-flowing forms such as powder or particles with sticker, inert diluent or lubricant, tensio-active agent or dispersant to be compressed.The making method of moulding tablet can be in suitable machine, the mixture with the moistening powdered compounds of inertia liquid diluent to be carried out moulding.Tablet is dressing or indentation randomly, and can be mixed with can slowly-releasing or the controlled release form of activeconstituents wherein.The dosage of all oral prepns should be fit to this administering mode.The crimping capsule can contain activeconstituents, and this activeconstituents can mix with weighting agent such as lactose, sticker such as starch and/or lubricant such as talcum powder or Magnesium Stearate and optional stablizer.In soft capsule, the active compound solubilized or be suspended in suitable liquid such as wax, whiteruss or liquid macrogol in.In addition, can add stablizer.Sugar-coat agent core body has suitable dressing.For this purpose, concentrated sugar solution can be used, wherein gum arabic, talcum powder, Vinylpyrrolidone polymer, carbomer gel, polyoxyethylene glycol and/or titanium oxide, lacquer solution and appropriate organic solvent or solvent mixture can be randomly contained.Can dyestuff or pigment be added in tablet or the dragee coatings, be used to indicate or characterize the various combination of active compound doses.

Can prepare through injection as inject or continuous infusion carries out the compound of parenteral admin.The preparation that is used to inject can be a unit dosage, for example is contained in ampoule or the multi-dose container, is added with sanitas.Said composition can be the form such as the suspension agent in oiliness or the aqueous carrier, solution or emulsion, can contain prescription reagent, like suspending agent, stablizer and/or dispersion agent.Can said preparation be provided with ampoule and the medicine bottle that unitary dose or multi-dose container for example seal; Also can powder type or preserve said preparation with freeze-dried (freeze-drying) condition, face with preceding needs adding sterile liquid supporting agent such as salt solution or aseptic pyrogen-free water and can use.The injection solution and the suspension that face usefulness can be prepared by sterilized powder, particle and the tablet that preamble is described.

The preparation that is used for parenteral admin comprises water-based and non-aqueous (oiliness) aseptic injectable solution of active compound, and it can comprise inhibitor, buffer reagent, fungistat and make preparation and the isoosmotic solute of blood of specifying the recipient; Water-based and non-aqueous sterile suspension, it can comprise suspending agent and thickening material.Suitable lipophilic solvent or supporting agent comprise wax such as til, or Acrawax such as OE or triglyceride level, or liposome.The water-based injection suspension can comprise the material that increases suspension viscosity, like Xylo-Mucine, Sorbitol Powder or DEXTRAN 500.000.Suspension can be chosen wantonly and comprise suitable stabilizers or increase the compound dissolution degree to prepare the reagent of highly enriched solution.

Except that previous formulations, compound also can be mixed with prolonged action preparation.This prolonged action preparation can be through implanting (for example subcutaneous or intramuscular is implanted) or intramuscular injection administration.Therefore, for example, compound also can be formulated together with suitable polymers material or hydrophobic material (for example, being mixed with emulsion with acceptable oil) or ion exchange resin, perhaps is mixed with the microsolubility verivate, for example, and slightly soluble salt.

For containing clothes or sublingual administration, compsn can adopt the form of tablet, lozenge, pastille or the gel of usual manner preparation.Said composition can be included in the activeconstituents in flavoured base such as sucrose and gum arabic or the tragacanth.

Compound also can be mixed with rectal compositions, and for example suppository or delay enema for example contain conventional suppository base, like theobroma oil, polyoxyethylene glycol or other glyceryl ester.

Some compound as herein described can topical, promptly non-general administration.This comprise with compound of the present invention be used for outward epidermis or mouthful cheek and with this compound be instilled in the ear, in intraocular and the nose, but compound can significantly not get into blood flow.On the contrary, the general administration is meant oral, intravenously, intraperitoneal and intramuscular administration.

The preparation that is applicable to topical comprises liquid or the semi-liquid preparations that is applicable to through skin arrival inflammation part, example gel, liniment, lotion, emulsifiable paste, ointment or paste, and the drops that is applicable to eye, ear or nasal administration.During topical administration, activeconstituents can account for for example 0.001% to 10%w/w (by weight) of preparation.In some embodiments, activeconstituents can account for up to 10%w/w.In other embodiment, it can account for less than 5%w/w.In some embodiments, activeconstituents can account for 2%w/w-5%w/w.In other embodiment, it can account for the 0.1%-1%w/w of said preparation.

During inhalation, compound can be sent by insufflator, atomizer pressurized tank or other mode of sending aerosol spray easily.Pressurized tank can comprise suitable propelling agent, like Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas.Under the situation of pressurised aerosol, can send metered amount through valve, to confirm dose unit.Perhaps, suck or when being blown into administration, The compounds of this invention can be the form of dry powder compositions, for example the powdered mixture of this compound and suitable powder base-material such as lactose or starch.Can powder composition be processed unit dosage, be contained in (for example) capsule or the cartridge case, perhaps (as) in gelatin or the Blister Package, can give this powder through assisting of sucker or insufflator.

Preferred unit dose formulations is the formulations of active ingredients that comprises effective dose (as mentioned below) or its suitable part.

It should be understood that and remove the above-mentioned composition of mentioning especially, above-mentioned preparation can also comprise other conventional dose with the relevant field of research preparation type, for example, is suitable for oral preparation and can comprises seasonings.

Compound can be with the oral dose or the drug administration by injection of 0.1-500 mg/kg/day.Adult's dosage range is generally 5 milligrams to 2 gram/skies.Tablet or other can comprise a certain amount of one or more compounds easily with the preparation that the individual form provides, and this dosage or a plurality of dosage are effective, for example comprise the 5-500 milligram, the unit of about usually 10-200 milligram.

Can with solid support material combination after obtain the amount of the activeconstituents of single dose form can be according to treatment the time host and concrete mode of administration change.

Compound can give with various patterns, for example oral, external application or through injection.The accurate amount that gives patient's compound is attending doctor's a responsibility.Concrete dosage level to any particular patient depends on various factors, comprises activity, age, body weight, general health situation, sex, diet, administration time, route of administration, drainage rate, drug regimen, the accurate disease of treatment and the indication or the severity of disease of treatment of the particular compound that is adopted.And route of administration can change according to illness and seriousness thereof.

In some example, possibly suit compound described herein (or its pharmacy acceptable salt, ester or prodrug) and another kind of therapeutical agent united and give.For example, if one of spinoff that the patient experienced of accepting one of compound described herein is a hypertension, then unites and give antihypertensive drug and the initial treatment agent is useful.Perhaps, only as an example, the treatment of one of compound described herein is renderd a service and can be strengthened (being that adjuvant self possibly only have minimum treatment benefit, during still with another therapeutical agent coupling, to patient's overall treatment benefit enhancing) through the administration adjuvant.Perhaps, only give an example, can be through one of compound described herein be improved the benefit that the patient obtains with the therapeutical agent (also comprising regimen) that also has the treatment benefit in addition.Only give an example, in relating to the treating diabetes that gives one of compound described herein, the treatment benefit of raising can realize through another Remedies for diabetes is provided to the patient equally.Under any circumstance, how disease, imbalance or the illness of no matter being treated be, adduction or patient that the wholistic therapy benefit that the patient obtained may simply be two kinds of therapeutical agents possibly obtain synergistic benefits.

The concrete non-limiting example of possible combined therapy agent comprises that use compound as herein described and at least a other are selected from down the reagent of group:

A) antidiabetic such as Regular Insulin, insulin derivates and stand-in; Insulin secretion stimulators such as sulfonylurea be glipizide, glyburide and glimepiride (Amaryl) for example; Pancreotropic hormone (insulinotropic) sulfonylurea receptors ligand such as meglitinide be Starsis and repaglinide (repaglinide) for example; Insulin sensitizers such as Protein-tyrosine-phosphatase-1B (PTP-1B) suppressor factor such as PTP-112; GSK3 (glycogen synthase kinase-3) suppressor factor such as SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR part such as GW-0791 and AGN-194204; Sodium dependent glucose cotransport suppressor factor such as T-1095; Glycogen phosphorylase A suppressor factor such as BAY R3401; Guanyl guanidine such as metformin; Alpha-glucosidase inhibitor such as acarbose; GLP-1 (glucagon-like-peptide-1), GLP-1 analogue such as pancreotropic hormone analogue (Exendin)-4 and GLP-1 stand-in; DPPIV (two peptide amido peptidase TV) suppressor factor such as DPP728, LAF237 (embodiment 1 of Vildagliptin (vildagliptin)-WO 00/34241), MK-0431, Sha Gelieting (saxagliptin), GSK23A; The AGE clastogen; Thiazolidine diketone derivative (lattice row ketone (glitazone)) is like U-721017E (pioglitazone) or rosiglitazone (rosiglitazone); With Fei Gelie ketone type PPAR delta agonists GI-262570 for example;

B) lipid-lowering agent such as 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor, for example lovastatin, pitavastatin, SV, pravastatin, Cerivastatin, mevastatin, Wei Luotating (velostatin), fluvastatin, RG 12561, atorvastatin, superstatin and day are cut down his spit of fland (rivastatin); Squalene synthetase inhibitor; FXR (method Buddhist nun's ester X acceptor) and LXR (liver X receptor) part; QUESTRAN; Special type of shellfish; Nicotinic acid and Frosst);

C) antiobesity agent or appetite stimulator such as PHENTERMINE; Leptin; Bromocriptine; Dexamphetamine; Amphetamine; Phenfluoramine; Isomeride; Sibutramine; Orlistat; Isomeride; Mazindol; Phentermine; Phendimetrazine; Diethylpropion; Fluoxetine; Wellbutrin; Topiramate (topiramate); Diethylpropion; Benzphetamine; Phenylpropanolamine or ecopipam (ecopipam); Ephedrine; Pseudoephedrine or cannabinoid receptor antagonists;

D) hypotensive agent is like medullary loop hydragog(ue) such as Uregit, furosemide and torasemide; Diuretic(s) such as thiazine derivative, chlorothiazide, hydrodiuril, amiloride; Angiotensin saccharase (ACE) suppressor factor such as benazepril, captopril, enalapril, fosinopril, lisinopril, RS-10085 (moexipril), perindopril (perinodopril), quinapril, ramipril and Trolapril; Na-K-ATP enzyme membrane pump inhibitor such as digoxin; Proteinase, kidney brush border neutral (NEP) suppressor factor such as Sai Aofen (thiorphan), terteo-Sai Aofen, SQ29072; ECE suppressor factor such as SLV306; ACE/NEP suppressor factor such as omapatrilat (omapatrilat), Sampatrilat (sampatrilat) and Fasidotril; Angiotensin n antagonist such as TCV-116, SKF-108566, irbesartan, losartan, telmisartan and valsartan, particularly valsartan; Hypertension fibrinogen inhibitor such as SPP-100, terlakiren, ditekiren (ditekiren), RO 66-1132, RO-66-116; Receptor, retarding agent such as acebutolol, atenolol USP 23, betaxolol, bisoprolol, metoprolol, nadolol, Proprasylyte, sotalol and timolol; Inotropic agent (inotropic agent) is like digoxin, dobutamine and milrinone; Calcium channel blocker such as Bepridil, amlodipine, diltiazem, felodipine, nicardipine, nimodipine, nisoldipine, nifedipine and verapamil; Aldosterone receptor antagonist; With the aldosterone synthetase inhibitors;

E) HDL increases compound;

F) the cholesterol absorption adjusting control agent is as according to Ezetimibe (etizimibe) and KT6-971;

G) Apo-Al analogue and stand-in;

H) thrombin inhibitors such as Xi Meijia crowd (Ximelagatran);

I) aldosterone suppressor factor such as Anastrozole (anastrazole), fadrozole (fadrazole) and eplerenone (eplerenone);

J) anticoagulant such as Asprin and SR-25990C;

K) oestrogenic hormon, testosterone, selective estrogen receptor adjusting control agent and selective androgen receptor adjusting control agent;

L) compound such as the pdgf receptor tyrosine kinase inhibitor such as the imatinib (miatinib) of chemotherapeutics such as aromatase inhibitor such as letrozole, estrogen antagonist, topoisomerase I suppressor factor, topoisomerase II suppressor factor, microtubule activator, alkylating agent, antineoplastic antimetabolite, platinic compound and reduction protein kinase activity; With

M) with the reagent of 5-HT3 acceptor interaction and/or with No. the 5510353rd, the reagent of 5-HT4 acceptor interaction such as USP in embodiment 13 described Tegaserods, toxilic acid list Tegaserod, cisapride and cilansetron.

Under any circumstance, multiple therapeutical agent (one of them is a compound disclosed herein at least) can be with random order or even administration simultaneously.If administration simultaneously, then multiple therapeutical agent can provide through single Unified Form or through a plurality of forms (only giving an example, like single pill or two independent pills).The a kind of of therapeutical agent can give by multiple doses, maybe can give by multiple doses.If not the while administration, then the timed interval between the multiple doses can be from several minutes to around scope in any time length.

Therefore; On the other hand; Some embodiment provides the method for the imbalance of treatment PASK mediation in human or animal's object of this treatment of needs; The a certain amount of compound as herein described that can effectively reduce or prevent the said imbalance of object of the said object of this method afford, optional and at least a other agent combination known in the art.In related fields, some embodiment provides therapeutic compsn, and it comprises other reagent that at least a compound as herein described and one or more are used to treat the imbalance of PASK mediation.

Recent research find to improve and to activate after the substratum glucose concn causes the translation of PASK.Proved that the active insulin expression institute for the glucose stimulation of PASK is essential, shown in the research in the PASK1 mouse.Proved that also the PASK disappearance causes the approaching resistance completely of the phenotype that high fat diet is caused, said phenotype comprises obesity, insulin resistance and the accumulation of liver fat.As if suppress can be for disease treatment provides effective therapeutic strategy to PASK, and said disease is for example diabetes B, general insulin resistance and metabolic syndrome.

Being characterized as of metabolic syndrome (being called metabolic syndrome X again) has following at least three kinds of symptoms: insulin resistance; Be defined as 40 inches of waistlines or bigger among stomach fat-male sex, among the women be 35 inches or bigger; After hyperglycemia level-fasting at least 110 milligrams/deciliters (mg/dL); At least 150mg/dL in high triglyceride-blood flow; Low HDL-be less than 40mg/dL; State (like high fibrinogen in the blood or inhibitors of plasminogen activator inhibitor) before the thrombosis; Or blood pressure 130/85mmHg or higher.Metabolic syndrome and other illnesss are related as finding between obesity, hypertension and the high-level LDL SUV, and these all are the cardiovascular disease risk factors.For example, there is the contact that increases between metabolic syndrome and the atherosclerosis.The people who suffers from metabolic syndrome also is more prone to take place diabetes B, and women's the PCOS (polycystic ovary syndrome) and the male sex's prostate cancer.

As stated, insulin resistance can comprise the diabetes B performance by several means.Diabetes B is the illness with the obvious relation between persistence of insulin resistance.Compensatory hyperinsulinism generally helped to keep the normal glucose level between decades, and tangible mellitus take place then.Final pancreatic beta cell can't overcome insulin resistance through hyperinsulinism.Glucose level rises, and is diagnosed as mellitus.The patient of diabetes B keeps hyperinsulinism and is in the terminal stage of a disease up to it.As stated, insulin resistance also can be relevant with hyperinsulinism.Half has insulin resistance and hyperinsulinism in the primary hypertension patient, and evidence suggests that blood pressure is relevant with the insulin resistance degree.Hyperlipidaemia is also related with insulin resistance.The serum C-VLDL that diabetes B patient's lipid profile comprises and the level of triglyceride level increase and the reduction of low-density lipoprotein triglyceride levels sometimes.The philtrum that hdl level is lower is found insulin resistance.Insulin level is also synthetic relevant with the plasma triglyceride level with vldl.

Therefore, also be disclosed in the object method of treatment insulin resistance, said method comprises that selection need treat the object of insulin resistance and give said object with the compound of the inhibition PASK of significant quantity.

The disease of the disease specific that compound as herein described, compsn and method are treated at least partly mediating by PASK.Therefore, method as herein described is used for: reduce the accumulation of object glycogen; Increase HDL or HDLc, reduction LDL or LDLc, the LDL particle size is become normal LDL, reduction VLDL, triglyceride reducing or suppresses cholesterol absorption the object from less density; Reduce insulin resistance, improve glucose utilization or reduce the object blood pressure; Reduce the interior fat of object; Reduce serum transaminase in the object; Reduce HbA1 c in the object; Or treatment disease; All all comprise the patient who the compound described herein of therapeutic dose is needed it.In another embodiment, disease to be treated can be metabolic trouble.In another embodiment, said metabolic trouble can be selected from: obesity, mellitus, particularly diabetes B, hyperinsulinemia, glucose do not tolerate, metabolic syndrome X, hyperlipemia, hypertriglyceridemia, hypercholesterolemia and hepatic steatosis.In other embodiments, disease to be treated can be selected from: cardiovascular disorder comprises vascular disease, atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure and peripheral vascular disease.In a preferred embodiment, aforesaid method can not cause bringing out of glycopenia state and keep.

In another embodiment, said metabolic trouble can be the neurological disease of known association metabolic trouble and/or insulin resistance, like alzheimer's disease.

In addition, PASK adjusting control agent described herein can be used for treating hyperplasia such as cancer.Blood and the non-hematologic cancers that can treat or prevent include but not limited to: multiple myeloma; Acute and chronic leukemia such as acute lymphoblastic leukemia (ALL), lymphocytic leukemia (CLL) and chronic marrow generation property white blood disease (CLL); Lymphoma such as Hodgkin lymphoma and non-Hodgkin lymphoma (low, neutralization height), the malignant tumour at brain, Head and Neck, breast, lung, reproductive tract, upper digestive tract, pancreas, liver, kidney, bladder, prostate gland and colon/rectum position.

Except being used for human body therapy, some compound as herein described and preparation also can be used for companion animals, external animal and farm-animals, comprise the veterinary treatment of Mammals, rodent etc.More preferably animal comprises horse, dog and cat.

Citing document

The tabulation of following this paper citing document, though comprehensively uninevitable, provide convenience to the reader.All reference, patent and patented claim that this paper quotes are included this paper in as a reference in full.If the guidance of these reference conflicts with the guidance of the clear statement of this paper, then be as the criterion with the present invention.

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The general compound method of preparation compound

Usually can adopt following scheme to come embodiment of the present invention.

Scheme I

Step 1.

Synthesizing of 4-fluoro-3-nitrobenzoic acid methyl esters4-fluoro-3-nitrobenzoic acid (10g in the 250-mL round-bottomed flask; 54.05mmol, 1.00 equivalents) methanol solution (60mL) in dropwise 0 ℃ stir to add THIONYL CHLORIDE 97 (6.5g, 54.62mmol; 1.01 equivalent), in oil bath, stirred 3 hours under the reflux conditions then.With the mixture vacuum concentration that obtains,, and use NaHCO with 100mL EtOAc dilution ₃(saturated) aqueous solution is 7-8 with pH regulator.Use this solution of 6x50mL ethyl acetate extraction then, merge organic layer and use anhydrous sodium sulfate drying, vacuum concentration obtains 12.42g (rough) 4-fluoro-3-nitrobenzoic acid methyl esters white solid then.

Step 2.

Synthesizing of 4-(2-methoxyl group-2-oxo-1-benzene ethylamino)-3-nitrobenzoic acid methyl esters.Be dissolved in 2-amino-2-phenylacetic acid methyl ester hydrochloride (2.5g of DMF (30mL); 12.38mmol; 1.00 solution equivalent), 4-fluoro-3-nitrobenzoic acid methyl esters (5g, 25.13mmol, 2.00 equivalents) and DIEA (5g; 38.76mmol, 3.13 equivalents) in the 100mL round-bottomed flask, spend the night in 30 ℃ of reactions.Then through adding the 200mL shrend reaction of going out, and pass through solid collected by filtration.Produce 3.82g (90%) 4-(2-methoxyl group-2-oxo-1-benzene ethylamino)-3-nitrobenzoic acid methyl esters yellow solid through silicagel column (sherwood oil/EtOAc (50: 1)) purifying.LC-MS(ES，m/z)：345[M+H] ⁺。

Step 3.

3-oxo-2-phenyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate methyl ester synthetic.Iron (34.89g, 623.04mmol, 5.00 equivalents) is added the 4-that is dissolved in methyl alcohol (300mL) (2-methoxyl group-2-oxo-1-benzene ethylamino)-3-nitrobenzoic acid methyl esters (42.87g, 124.62mmol, 1.00 equivalents) and the water-based NH in stirring in batches ₄(5.00 equivalents are in solution 80mL) for 32.1g, 600.00mmol for Cl.The solution reflux that obtains 5 hours.After the cooling solid is leached.With the filtrating vacuum concentration that obtains, obtain 19.81g (56%) 3-oxo-2-phenyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate methyl ester yellow solid.LC-MS(ES，m/z)：283[M+H] ⁺。

Step 4.

3-oxo-2-phenyl-3,4-dihydro-quinoxaline-6-carboxylate methyl ester synthetic.DDQ (21.25g, 93.6mmol, 2.62 equivalents) adding is dissolved in two

3-oxo-2-the phenyl-1,2,3 of alkane (750mL), in the solution of 4-tetrahydroquinoxaline-6-carboxylate methyl ester (10.07g, 35.7mmol, 1.00 equivalents) while stirring room temperature reaction spend the night.Solid collected by filtration.Use 2x500mL K ₂CO ₃(saturated) aqueous solution cleans filter cake.Produce 7.29g (rough) 3-oxo-2-phenyl-3,4-dihydro-quinoxaline-6-carboxylate methyl ester pale solid.LC-MS(ES，m/z)：281[M+H] ⁺。

Step 5.

Synthesizing of 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester.Be dissolved in CH in the 1000mL round-bottomed flask ₃3-oxo-2-phenyl-3 of CN (120mL), 4-dihydro-quinoxaline-6-carboxylate methyl ester (2.1g, 7.50mmol, 1.00 equivalents) and POBr ₃Reflux spends the night in (21.5g, 74.91mmol, 10.00 equivalents) solution oil bath.With the mixture vacuum concentration that obtains, be 7-8 with sodium hydrogencarbonate (saturated) aqueous solution with pH regulator, and with this solution of 4x100mL dichloromethane extraction.Merge organic layer,, produce 2g (78%) 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester white solid with anhydrous sodium sulfate drying and vacuum concentration.LC-MS(ES，m/z)：343[M+H] ⁺。 ¹H-NMR(300MHz，DMSO-d ₆)8.620-8.615(d，J＝1.5Hz，1H)，8.38-8.35(q，J＝3.3Hz，1H)，8.28-8.25(d，J＝8.7Hz，1H)，7.85-7.82(q，J＝6Hz，2H)，7.60-7.58(t，J＝2.4Hz，3H)，3.99(s，3H)。

R wherein ₁And R ₂Be selected from alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl and amino independently of one another, wherein any group all can be optionally substituted; And R ₃Be selected from hydrogen and the alkyl that can be optionally substituted.

The present invention further illustrates through following embodiment, and said embodiment can accomplish and without undo experimentation through method as herein described or by those skilled in the art, or can commercially availablely buy.Possibly use following abbreviation in the whole experimental program.Following table is provided is for ease rather than comprise all.

Abbreviation/initial	Implication
		Ar	Aryl
Pd ₂(dba) ₃	Three (dibenzalacetones), two palladiums (0)
		BINAP	2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene
NaOt-Bu	Sodium tert-butoxide
		PE	Sherwood oil
EA	ETHYLE ACETATE
		DCM	Methylene dichloride
TFA	Trifluoroacetic acid
		AcOH	Acetate
DMF	N, dinethylformamide
		DIEA	N, the N-diisopropylethylamine
MeOH	Methyl alcohol
		THF	THF
BOC	The N-tert-butoxycarbonyl
		Tol	Toluene
DMSO	Methyl-sulphoxide
		PCy3	Tricyclohexyl phosphine
TLC	Tlc
		X-Phos	2-dicyclohexylphosphontetrafluoroborate-2 ', 4 ', 6 '-tri isopropyl biphenyl
DDQ	2,3-two chloro-5,6-dicyano benzoquinone

Embodiment 1

2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperazine-1-yl) quinoxaline-6-carboxylic acid

Step 1.4-(4-(trifluoromethyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester

With piperazine-1-carboxylic acid tert-butyl ester (1.52g, 8.17mmol, 2.00 equivalents), 1-bromo-4-(trifluoromethyl) benzene (1g, 4.10mmol, 1.00 equivalents), BINAP (124mg, 0.40mmol, 0.10 equivalent), Pd ₂(dba) ₃(184mg, 0.20mmol, 0.05 equivalent), NaOt-Bu (1.2g, 12.50mmol, 3.00 equivalents) and toluene (15mL) merge in the 100-mL round-bottomed flask stirred overnight and vacuum concentration in 100 ℃ of oil baths.Silicagel column purifying through with PE/EA (50: 1) produces 1.06g (78%) 4-(4-(trifluoromethyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester yellow solid.

LC-MS(ES，m/z)：331[M+H]+

Step 2.1-(4-(trifluoromethyl) phenyl) piperazine

4-(4-(trifluoromethyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester (1.06g, 3.21mmol, the 1.00 equivalents) solution that will be dissolved in methylene dichloride (10mL) and trifluoroacetic acid (6mL) places the 50mL round-bottomed flask and stirred 2 hours in 30 ℃ of oil baths.Use saturated aqueous solution of sodium bicarbonate that the pH regulator of this solution is 7-8.The solution that obtains is used the 4x30mL dichloromethane extraction, merges organic layer and uses anhydrous sodium sulfate drying, solids removed by filtration then.The solution for vacuum concentration that obtains obtains 740mg (rough) 1-(4-(trifluoromethyl) phenyl) piperazine yellow solid.

LC-MS(ES，m/z)：231[M+H]+。

Step 3.2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester

To be dissolved in 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg of DMF (8mL); 0.44mmol; 1.00 equivalent) solution, 1-(4-(trifluoromethyl) phenyl) piperazine (202mg, 0.88mmol, 2.00 equivalents), DIEA (170.3mg; 1.32mmol, 3.00 equivalents) and place the 20-mL ST and in 100 ℃ of oil bath stirred overnight.Then through adding the shrend reaction of going out.The solution that obtains merges organic layer and uses anhydrous sodium sulfate drying, solids removed by filtration then with 4x 50mL ethyl acetate extraction.With the mixture vacuum concentration that obtains, obtain 177.4mg (78%) 2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS(ES，m/z)：492[M+H]+。

Step 4.2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperazine-1-yl) quinoxaline-6-carboxylic acid

To be dissolved in methyl alcohol/THF (1: 1) 2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester (137.7mg (10mL); 0.28mmol; 1.00 the sodium hydroxide (56mg of solution and water-soluble (3mL) equivalent); 1.40mmol, 5.00 equivalents) place the 50mL round-bottomed flask and stirred 2 hours in 40 ℃ of oil baths.Vacuum concentrated mixture also filters.With the solution for vacuum concentration that obtains, and the solid that obtains with DCM/MeOH (5: 1) cleaning obtains 45mg (33%) 2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperazine-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：478[M+H]+

¹H-NMR(300MHz，DMSO，ppm)δ13.37(1H，s)，8.341(1H，s)，8.029(4H，s)，7.578，7.566(4H，d，J＝6.3Hz)，7.528，7.499(2H，d，J＝8.7Hz)，7.101，7.072(2H，d，J＝8.7Hz)，3.367(8H，s).

Embodiment 2

2-phenyl-3-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid

Step 1.4-(pyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester

To be dissolved in 2-bromopyridine (1.0g, 6.33mmol, 1.00 equivalents), piperazine-1-carboxylic acid tert-butyl ester (2.35g, 12.62mmol, 2.00 equivalents), BINAP (196mg, 0.63mmol, 0.10 equivalent), the Pd of toluene (20mL) ₂(dba) ₃The solution of (290mg, 0.32mmol, 0.05 equivalent) and NaOt-Bu (1.89g, 18.90mmol, 3.00 equivalents) places the 100-mL round-bottomed flask in the following 100 ℃ of oil bath stirred overnight of inert atmosphere.The mixture of vacuum concentration gained.Produce 1.4g (84%) 4-(pyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester yellow solid through silicagel column (ethyl acetate/petroleum ether (1: 40)) purifying.

Step 2.1-(pyridine-2-yl) piperazine

To be dissolved in DCM/CF ₃The 4-of COOH (10/3mL) (pyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester (500mg, 1.90mmol, 1.00 equivalents) solution places the 50mL round-bottomed flask and stirred 1 hour in 30 ℃ of oil baths.(1M) is adjusted to 9 with pH value of solution with aqueous sodium hydroxide solution, uses the 3x10mL dichloromethane extraction then.Merge organic layer, with anhydrous sodium sulfate drying and solids removed by filtration.The solution for vacuum concentration that obtains obtains 300mg (97%) 1-(pyridine-2-yl) piperazine yellow oil.

Step 3.2-phenyl-3-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester

To be dissolved in 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (50mg of DMF (10mL); 0.15mmol; 1.00 equivalent), 1-(pyridine-2-yl) piperazine (50mg, 0.31mmol, 2.00 equivalents) and DIEA (100mg; 0.78mmol, 3.00 equivalents) solution place the 20-mL ST and in the following 100 ℃ of oil bath stirred overnight of inert atmosphere vacuum concentration then.Produce 68mg (rough) 2-phenyl-3-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid through silicagel column (ethyl acetate/petroleum ether (1: 10)) purifying.

Step 4.2-phenyl-3-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid

To be dissolved in 2-phenyl-3-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester (100mg of methyl alcohol (10mL); 0.24mmol; 1.00 equivalent) and sodium hydroxide (47mg, 1.18mmol, 5.00 equivalents) solution place the 100mL round-bottomed flask and stirred 2 hours in 50 ℃ of oil baths.(1M) is adjusted to 4-5 with pH value of solution with hydrochloric acid, uses the 3x10mL dichloromethane extraction then.Merge organic layer and vacuum concentration and produce 80mg (83%) 2-phenyl-3-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：412[M+H]+

¹H-NMR(300MHz，CDCl ₃，ppm)δ8.507(s，1H)，7.970-8.159(m，5H)，7.574-7.617(m，4H)，6.846-6.875(m，1H)，6.694-6.733(m，1H)，3.540-3.559(m，4H)，3.437-3.454(m，4H).

Embodiment 3

3-(4-(3-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.4-(3-chloro-phenyl-) piperazine-1-carboxylic acid tert-butyl ester

With piperazine-1-carboxylic acid tert-butyl ester (1.96g, 10.54mmol, 2.00 equivalents), 1-bromo-3-chlorobenzene (1g, 5.26mmol, 1.00 equivalents), BINAP (330mg, 0.53mmol, 0.10 equivalent), Pd ₂(dba) ₃(243.8mg, 0.27mmol, 0.05 equivalent), NaOt-Bu (1.59g, 16.56mmol, 3.00 equivalents) and toluene (17mL) solution place the 100-mL round-bottomed flask in 100 ℃ of oil bath stirred overnight and vacuum concentration.Silicagel column purifying through with PE/EA (50: 1) produces 1.3g (83%) 4-(3-chloro-phenyl-) piperazine-1-carboxylic acid tert-butyl ester yellow solid.

LC-MS(ES，m/z)：297[M+H]+

Step 2.1-(3-chloro-phenyl-) piperazine

4-(4-p-methoxy-phenyl) piperazine-1-carboxylic acid tert-butyl ester (1.3g, 4.39mmol, the 1.00 equivalents) solution that will be dissolved in methylene dichloride (11mL) and trifluoroacetic acid (6mL) places the 50mL round-bottomed flask and stirred 3 hours in 20 ℃ of oil baths.Use saturated aqueous solution of sodium bicarbonate that the pH regulator of this solution is 7-8, and use the 6x15mL dichloromethane extraction.Merge organic layer, with anhydrous sodium sulfate drying and solids removed by filtration, vacuum concentration produces 430mg (50%) 1-(3-chloro-phenyl-) piperazine yellow solid then.

LC-MS(ES，m/z)：197[M+H]+

Step 3.3-(4-(3-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg of DMF (4mL); 0.44mmol, 1.00 equivalents), 1-(3-chloro-phenyl-) piperazine (172.5mg, 0.88mmol; 2.00 equivalent) and DIEA (170.3mg; 1.32mmol, 3.00 equivalents) and solution places the 20-mL ST and in 100 ℃ of oil bath stirred overnight, water cancellation then.The solution that obtains is used the 6x20mL ethyl acetate extraction, merges organic layer and uses anhydrous sodium sulfate drying, solids removed by filtration and vacuum concentration then.Produce 186.7mg (89%) 3-(4-(3-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid through silicagel column (PE/EA (30: 1)) purifying.

LC-MS(ES，m/z)：459[M+H]+

Step 4.3-(4-(3-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in THF/MeOH (1: 1) 3-(4-(3-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (186.7mg (25mL); 0.41mmol; 1.00 equivalent) and sodium hydroxide (82mg; 2.05mmol, 5.00 equivalents) and solution places the 50mL round-bottomed flask and stirred 8 hours in 50 ℃ of oil baths, vacuum concentration then.Produce 177.7mg (95%) 3-(4-(3-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：445[M+H]+

¹H-NMR(300MHz，DMSO，ppm)δ8.340(1H，s)，8.029(4H，s)，7.587，7.565(3H，d，J＝6.6Hz)，7.217，7.190(1H，d，J＝8.1Hz)，6.972，6.935(2H，d，J＝11.1Hz)，6.818，6.789(2H，d，J＝8.7Hz)，3.3.246(4H，s).

Embodiment 4

3-(4-N-METHYL PIPERAZINE-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(4-N-METHYL PIPERAZINE-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, the 1.00 equivalents) solution and the 1-N-METHYL PIPERAZINE (90mg, 0.90mmol, 2.00 equivalents) that are dissolved in DMSO (8mL) stirred 2 hours in 125 ℃ of oil baths in the 20-mL ST.The solution that obtains is with the DCM/H of 20ml ₂O (1: 1) dilution, the DCM extraction with 4x40mL merges organic layer then.Use Na ₂SO ₄Dry said mixture, solids removed by filtration, vacuum concentration produces 200mg (rough) 3-(4-N-METHYL PIPERAZINE-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester brown solid then.

LC-MS(ES，m/z)：363[M+H]+

Step 2.3-(4-N-METHYL PIPERAZINE-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in THF/MeOH (1: 1) 3-(4-N-METHYL PIPERAZINE-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (249.7mg (20mL); 0.55mmol; 1.00 equivalent) sodium hydroxide of solution and water-soluble (1.5mL) (138mg, 3.45mmol, 5.00 equivalents) places the 50mL round-bottomed flask; Stirred 3 hours in 30 ℃ of oil baths, vacuum concentration also cleans with DCM.Produce 90mg (45%) 3-(4-N-METHYL PIPERAZINE-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：348[M+H]+

¹H-NMR(300MHz，DMSO，ppm)8.355(1H，s)，8.083-8.017(4H，t)，8.585-8.572(3H，d，J＝3.9Hz)，3.341-3.202(8H，d，J＝41.7Hz)，2.737(3H，s).

Embodiment 5

2-phenyl-3-(piperazine-1-yl) quinoxaline-6-carboxylic acid

Step 1.2-phenyl-3-(piperazine-1-yl) quinoxaline-6-carboxylate methyl ester

To be dissolved in 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg of DMSO (8mL); 0.44mmol, 1.00 equivalents) and piperazine (77.4mg, 0.90mmol; 2.00 equivalent) solution places the 20-mL ST and stirred 3 hours in 125 ℃ of oil baths, adds the 50mL shrend then and goes out.The solution that obtains is used the 6x50mL dichloromethane extraction, merges organic layer and uses anhydrous sodium sulfate drying, and filtering solution is removed solid then.Vacuum concentration obtains 160mg (91%) 2-phenyl-3-(piperazine-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS(ES，m/z)：348[M+H]+

Step 2.2-phenyl-3-(piperazine-1-yl) quinoxaline-6-carboxylic acid

To be dissolved in THF/MeOH (1: 1) 2-phenyl-3-(piperazine-1-yl) quinoxaline-6-carboxylate methyl ester (160mg (20mL); 0.42mmol; 1.00 equivalent) sodium hydroxide of solution and water-soluble (1.5mL) (91.9mg, 2.30mmol, 5.00 equivalents) solution places the 50mL round-bottomed flask; Stirred 3 hours in 30 ℃ of oil baths, then vacuum concentration.Resistates is dissolved in 4mL DMSO, and produces 42mg (29%) 2-phenyl-3-(piperazine-1-yl) quinoxaline-6-carboxylic acid yellow solid through silicagel column (DCM/MeOH (5: 1)) purifying.

LC-MS(ES，m/z)：334[M+H]+

¹H-NMR(300MHz，DMSO，ppm)8.346-8.342(1H，d，H＝1.2Hz)，8.150(1H，s)，8.054-8.007(3H，q)，7.584-7.560(3H，t)，3.420(4H，s)，3.112(4H，s).

Embodiment 6

2-phenyl-3-(4-phenylpiperazine-1-yl) quinoxaline-6-carboxylic acid

Step 1.4-phenylpiperazine-1-carboxylic acid tert-butyl ester

To be dissolved in 1-bromobenzene (1g, 6.37mmol, 1.00 equivalents), piperazine-1-carboxylic acid tert-butyl ester (2.35g, 12.62mmol, 2.00 equivalents), BINAP (196mg, 0.63mmol, 0.10 equivalent), the Pd of toluene (20mL) ₂(dba) ₃The solution of (290mg, 0.32mmol, 0.05 equivalent) and NaOt-Bu (1.89g, 18.90mmol, 3.00 equivalents) places 100-mL 3 neck round-bottomed flasks in the following 100 ℃ of oil bath stirred overnight of inert atmosphere.The mixture vacuum concentration that obtains also passes through silicagel column (ethyl acetate/petroleum ether (1: 40)) purifying generation 1.3g (78%) 4-phenylpiperazine-1-carboxylic acid tert-butyl ester yellow solid.

Step 2.1-phenylpiperazine

To be dissolved in DCM/CF ₃4-phenylpiperazine-1-carboxylic acid tert-butyl ester of COOH (10/3mL) (500mg, 1.91mmol, 1.00 equivalents) solution places the 50mL round-bottomed flask and stirred 1 hour in 30 ℃ of oil baths.(1M) is adjusted to 9 with pH value of solution with aqueous sodium hydroxide solution, and with this solution of 3x10mL dichloromethane extraction, merges organic layer then and use anhydrous sodium sulfate drying.Solids removed by filtration, the solution for vacuum concentration that obtains produce 300mg (97%) 1-phenylpiperazine yellow oil.

Step 3.2-phenyl-3-(4-phenylpiperazine-1-yl) quinoxaline-6-carboxylate methyl ester

Be dissolved in adding 1-phenylpiperazine (50mg, 0.31mmol, 2.00 equivalents) and DIEA (100mg, 0.78mmol, 5.3 equivalents) in the 3-bromo-2-phenyl quinoxaline of DMF (10mL)-6-carboxylate methyl ester (50mg, 0.15mmol, 1.00 equivalents) solution.The solution that obtains is placed the 20mL ST, in 100 ℃ of oil bath stirred overnight, vacuum concentration then.Produce 70mg (rough) 2-phenyl-3-(4-phenylpiperazine-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid through silicagel column (ethyl acetate/petroleum ether (1: 10)) purifying.

Step 4.2-phenyl-3-(4-phenylpiperazine-1-yl) quinoxaline-6-carboxylic acid

To be dissolved in 2-phenyl-3-(4-phenylpiperazine-1-yl) quinoxaline-6-carboxylate methyl ester (100mg of methyl alcohol (10mL); 0.24mmol; 1.00 equivalent) and sodium hydroxide (47mg, 1.18mmol, 5.00 equivalents) solution place the 100mL round-bottomed flask and stirred 2 hours in 50 ℃ of oil baths.Is 4-5 with hydrochloric acid (1M) with the pH regulator of this solution.The solution that obtains is used the 3x10mL dichloromethane extraction, merges organic layer and vacuum concentration and produces 70mg (72%) 2-phenyl-3-(4-phenylpiperazine-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：411[M+H]+

¹H-NMR(300MHz，CDCl ₃，ppm)δ8.472(s，1H)，8.118-8.147(m，1H)，8.009-8.041(m，2H)，7.923-7.952(m，1H)，7.536-7.596(m，3H)，7.218-7.271(m，2H)，6.961-6.987(m，2H)，6.830-6.879(m，1H)，3.434-3.466(m，4H)，3.170-3.202(m，4H).

Embodiment 7

2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid

Step 1.4-(4-(trifluoromethyl) phenyl) pyridine

To be dissolved in 1,4-two

1-bromo-4-(trifluoromethyl) benzene (1.0g, 4.44mmol, 1.00 equivalents) of alkane (10mL), 4-pyridine boric acid (820mg, 6.67mmol, 1.50 equivalents), PCy ₃(156mg, 0.56mmol, 0.14 equivalent), Pd ₂(dba) ₃(220mg, 0.24mmol, 0.06 equivalent) and K ₃PO ₄The solution of (2.5g, 11.79mmol, 3.00 equivalents) places the 20-mL ST in inert atmosphere following 100 ℃ of oil bath stirred overnight, vacuum concentration then.Produce 1.2g (rough) 4-(4-(trifluoromethyl) phenyl) pyridine yellow solid through silicagel column (ethyl acetate/petroleum ether (1: 20)) purifying.

Step 2.4-(4-(trifluoromethyl) phenyl) piperidines

4-in the methyl alcohol (50mL) (4-(trifluoromethyl) phenyl) pyridine (500mg, 2.24mmol, 1.00 equivalents), CF ₃COOH (1.27g, 11.14mmol, 5.00 equivalents) and palladium carbon (100mg, 5%) suspension-s are in H ₂(g) hydrogenation is spent the night in the following 30 ℃ of oil baths of atmosphere.Filter this reaction mixture and use washed with methanol, vacuum concentration then.With aqueous sodium hydroxide solution (1M) the pH value of this solution is adjusted to 8-9.The solution that obtains is used the 3x20mL dichloromethane extraction, merges organic layer and vacuum concentration and produces 350mg (68%) 4-(4-(trifluoromethyl) phenyl) piperidines brown oil.

LC-MS(ES，m/z)[M+H] ⁺：230

Step 3.2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester

To be dissolved in 4-(4-(trifluoromethyl) phenyl) piperidines (200mg of DMF (10mL); 0.87mmol; 2.00 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents) and DIEA (169mg equivalent); 1.31mmol, 3.00 equivalents) and solution places the 20-mL ST and in 100 ℃ of oil bath stirred overnight.The mixture vacuum concentration that obtains also passes through silicagel column (ethyl acetate/petroleum ether (1: 20)) purifying generation 180mg (84%) 2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

Step 4.2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid

To be dissolved in 2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester (50mg of methyl alcohol (10mL); 0.10mmol; 1.00 equivalent) and sodium hydroxide (20mg; 0.50mmol, 5.00 equivalents) and solution places the 50mL round-bottomed flask and stirred 2 hours in 50 ℃ of oil baths.With aqueous sodium hydroxide solution (1M) the pH value of this solution is adjusted to 4-5.The solution that obtains is used the 3x10mL dichloromethane extraction, merges organic layer and vacuum concentration, through preparation type TLC (DCM: CH ₃OH 10: 1) purifying produces 25mg (51%) 2-phenyl-3-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid white solid.

LC-MS(ES，m/z)：478[M+H]+

¹H-NMR(300MHz，CDCl ₃，ppm)δ8.319(s，1H)，7.964-8.056(m，4H)，7.496-7.688(m，7H)，3.862-3.906(m，2H)，2.862-2.934(m，4H)，1.770(m，3H).

Embodiment 8

3-(4-(4-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.4-(4-chloro-phenyl-) piperazine-1-carboxylic acid tert-butyl ester

With the 1-bromo-4-chlorobenzene (500mg, 2.63mmol, 1.00 equivalents) in the toluene (20mL), piperazine-1-carboxylic acid tert-butyl ester (725mg, 3.90mmol, 1.50 equivalents), BINAP (48.6mg, 0.08mmol, 0.03 equivalent), Pd ₂(dba) ₃The suspension-s of (23.9mg, 0.03mmol, 0.01 equivalent) and NaOt-Bu (780mg, 8.12mmol, 3.00 equivalents) places the 50-mL round-bottomed flask in 100 ℃ of oil bath stirred overnight and vacuum concentration.Silicagel column purifying through with PE/EA (50: 1) produces 360.6mg (46%) 4-(4-chloro-phenyl-) piperazine-1-carboxylic acid tert-butyl ester yellow solid.

LC-MS(ES，m/z)：297[M+H]+

Step 2.1-(4-chloro-phenyl-) piperazine

Dropwise trifluoroacetic acid (3ml) is added while stirring under 0 ℃ and be dissolved in 4-(4-chloro-phenyl-) piperazine-1-carboxylic acid tert-butyl ester (360.6mg, 1.21mmol, 1.00 equivalents) solution of methylene dichloride (12mL).Gained solution stirred 3 hours in 20 ℃ of oil baths.Use saturated solution of sodium bicarbonate that the pH regulator of this solution is 7-8.The solution that obtains is used the 6x20mL dichloromethane extraction, merges organic layer and uses anhydrous sodium sulfate drying, vacuum concentration then.Produce 264.5mg (102%) 1-(4-chloro-phenyl-) piperazine yellow solid.

LC-MS(ES，m/z)：197[M+H]+

Step 3.3-(4-(4-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg of DMF (4mL); 0.44mmol, 1.00 equivalents), 1-(4-chloro-phenyl-) piperazine (172.5mg, 0.88mmol; 5.00 equivalent) and DIEA (170.3mg; 1.32mmol, 3.00 equivalents) and solution places the 8-mL ST and in 100 ℃ of oil bath stirred overnight, vacuum concentration then.Produce 153.4mg (69%) 3-(4-(4-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid through silicagel column (ethyl acetate/petroleum ether (1: 50)) purifying.

LC-MS(ES，m/z)：459[M+H]+

Step 4.3-(4-(4-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in THF/MeOH (1: 1) 3-(4-(4-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (153.4mg (12mL); 0.33mmol; 1.00 equivalent) and sodium hydroxide (66mg; 1.65mmol, 5.00 equivalents) and solution places the 50mL round-bottomed flask and stirred 5 hours in 50 ℃ of oil baths.Use 1N hydrochloric acid that the pH regulator of this solution is 3-4 and vacuum concentration.The solid that obtains with washed with methanol produces 47mg (31%) 3-(4-(4-chloro-phenyl-) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：445[M+H]+

¹H-NMR(300MHz，DMSO，ppm)δ13.305(1H，s)，8.342(1H，s)，8.031(4H，s)，7.585，7.566(3H，d，J＝5.7Hz)，7.256，7.228(2H，d，J＝8.4Hz)，6.984，6.956(2H，d，J＝8.4Hz)，3.359(4H，s)，3.204(4H，s).

Embodiment 9

3-(4-(4-p-methoxy-phenyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.4-(4-p-methoxy-phenyl) piperazine-1-carboxylic acid tert-butyl ester

With the piperazine in the toluene (15mL)-1-carboxylic acid tert-butyl ester (2g, 10.75mmol, 2.00 equivalents), 1-bromo-4-anisole (1g, 5.38mmol, 1.00 equivalents), X-phos (257.2mg, 0.54mmol, 0.10 equivalent), Pd ₂(dba) ₃(248.4mg, 0.27mmol, 0.05 equivalent), NaOt-Bu (1.62g, 16.88mmol, 3.00 equivalents) suspension-s place the 100-mL round-bottomed flask in 100 ℃ of oil bath stirred overnight vacuum concentration then.Produce 1.412g (81%) 4-(4-p-methoxy-phenyl) piperazine-1-carboxylic acid tert-butyl ester yellow solid through silicagel column (PE/EA (50: 1)) purifying.

LC-MS(ES，m/z)：293[M+H]+

Step 2.1-(4-p-methoxy-phenyl) piperazine

4-(4-p-methoxy-phenyl) piperazine-1-carboxylic acid tert-butyl ester (1.412g, 4.84mmol, 1.00 equivalents) solution and the trifluoroacetic acid (6mL) that will be dissolved in methylene dichloride (17mL) places the 50mL round-bottomed flask and stirred 2 hours in 20 ℃ of oil baths.Use saturated aqueous solution of sodium bicarbonate that the pH regulator of this solution is 7-8.The mixture vacuum concentration that obtains produces 0.92g (65%) 1-(4-p-methoxy-phenyl) piperazine yellow solid.

LC-MS(ES，m/z)：193[M+H]+

Step 3.3-(4-(4-p-methoxy-phenyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (200mg of DMF (6mL); 0.58mmol, 1.00 equivalents), 1-(4-p-methoxy-phenyl) piperazine (230.4mg, 1.20mmol; 2.00 equivalent) and DIEA (232.3mg; 1.80mmol, 3.00 equivalents) and solution places the 20-mL ST and in 100 ℃ of oil bath stirred overnight, vacuum concentration then.Produce 117.1mg (42%) 3-(4-(4-p-methoxy-phenyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid through the preparation HPLC purifying.

LC-MS(ES，m/z)：455[M+H]+

Step 4.3-(4-(4-p-methoxy-phenyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in 3-(4-(4-p-methoxy-phenyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (117.1mg of methyl alcohol (15mL); 0.26mmol; 1.00 equivalent) and sodium hydroxide (51.6mg, 1.29mmol, 5.00 equivalents) solution place the 50mL round-bottomed flask and stirred 5 hours in 50 ℃ of oil baths.Use 1N hydrochloric acid that the pH regulator of this solution is 3-4 and vacuum concentration.The solid that obtains with washed with methanol produces 80mg (70%) 3-(4-(4-p-methoxy-phenyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：441[M+H]+

¹H-NMR(300MHz，DMSO，ppm)δ13.330(1H，s)，8.331(1H，s)，8.019(4H，s)，7.579，7.557(3H，d，J＝6.6Hz)，6.922-6.802(4H，q，J＝9Hz)，3.683(4H，s)，3.068(4H，s).

Embodiment 10

3-(4-(3-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

step 1.3-(4-(3-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg of DMF (4mL); 0.44mmol; 1.00 equivalent), 4-(3-chloro-phenyl-) piperidine hydrochlorate (204.2mg, 0.88mmol, 2.00 equivalents) and DIEA (194.8mg; 1.51mmol, 5 equivalents) and solution places the 8-mL ST and in 100 ℃ of oil bath stirred overnight.Then through adding shrend go out reaction, vacuum concentration then.Produce 143.5mg (64%) 3-(4-(3-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid through silicagel column (ethyl acetate/petroleum ether (1: 100)) purifying.

LC-MS(ES，m/z)：457[M+H]+

Step 2.3-(4-(3-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

At the 3-that is dissolved in methyl alcohol (15mL) (4-(3-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (143.5mg; 0.29mmol, 1.00 equivalents, 91%) solution in dropwise stir to add the sodium hydroxide (62.8mg of water-soluble (2mL); 1.57mmol, 5.00 equivalents) and solution.Stirred overnight, vacuum concentration then in 50 ℃ of oil baths of the solution that obtains.The solid that obtains with washed with methanol produces 44mg (34%) 3-(4-(3-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：443[M+H]+

¹H-NMR(300MHz，DMSO，ppm)δ13.272(1H，s)，8.312(1H，s)，8.050-8.000(4H，t)，7.611-7.528(3H，t)，7.370-7.228(4H，m)3.941-3.864(2H，t)，2.907-2.717(3H，m)，1.738-1.631(4H，t).

Embodiment 11

3-(4-(4-p-methoxy-phenyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(4-(4-p-methoxy-phenyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in 3-chloro-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg of DMF (4mL); 0.50mmol; 1.00 equivalent), 4-(4-p-methoxy-phenyl) piperidines (191mg, 1.00mmol, 2.00 equivalents) and DIEA (194.8mg; 1.51mmol, 5.00 equivalents) and solution places the 8-mL ST and in 100 ℃ of oil bath stirred overnight.Then through adding the shrend reaction of going out, the mixture vacuum concentration that obtains.Produce 179.6mg (63%) 3-(4-(4-p-methoxy-phenyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid through silicagel column (ethyl acetate/petroleum ether (1: 50)) purifying.

LC-MS(ES，m/z)：454[M+H]+

Step 2.3-(4-(4-p-methoxy-phenyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

At the 3-that is dissolved in methyl alcohol (17mL) (4-(4-p-methoxy-phenyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (179.6mg; 0.36mmol, 1.00 equivalents, 90%) dropwise stir the sodium hydroxide (80mg that adds water-soluble (2mL) in the solution; 2.00mmol, 5.00 equivalents) and solution.The solution that obtains stirred 7 hours in 50 ℃ of oil baths, with 1N hydrochloric acid pH value of solution was adjusted to 3-4 then.With the mixture vacuum concentration that obtains, produce 81.9mg (50%) 3-(4-(4-p-methoxy-phenyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid with washed with methanol then.

LC-MS(ES，m/z)：440[M+H]+

¹H-NMR(300MHz，DMSO，ppm)δ8.302(1H，s)，8.035-7.991(4H，m)，7.607-7.519(3H，m)，7.177，7.148(2H，d，J＝8.7Hz)，6.873-6.844(2H，d，J＝8.7Hz)，3.889，3.846(2H，d，J＝12.9Hz)，3.717(3H，s)，2.899-2.825(2H，t)，2.661-2.610(1H，t)，1.732-1.619(4H，m).

Embodiment 12

2-phenyl-3-(piperidines-1-yl) quinoxaline-6-carboxylic acid

3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (200mg, 0.58mmol, 1.00 equivalents) piperidines (149mg, 1.75mmol, 3.01 equivalents), salt of wormwood (404mg, 2.93mmol, 5.02 equivalents), water (1mL) and DMF (3mL) are added in the 8-mL ST.100 ℃ of stirred overnight of the mixture that obtains.The mixture of vacuum concentration gained.Residue is dissolved in the 20mL water.(1mol/L) is adjusted to 5 with this pH value of aqueous solution with hydrogenchloride.Filter and collect solid and the water cleaning that obtains, dry in the baking oven of decompression then.Produce 105mg (54%) 2-phenyl-3-(piperidines-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：334[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.28(d，J＝1.2Hz，1H)，8.02-7.94(m，4H)，7.60-7.52(m，3H)，3.22(s，4H)，1.53(s，6H).

Embodiment 13

2-phenyl-3-(4-Phenylpiperidine-1-yl) quinoxaline-6-carboxylic acid

Step 1.2-phenyl-3-(4-Phenylpiperidine-1-yl) quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents), 4-Phenylpiperidine (141.68mg; 0.88mmol, 2.00 equivalents), DIEA (170.3mg, 1.32mmol; 3.00 equivalent) and N, dinethylformamide (4mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With PE/EA (100: 1) residue is put on silicagel column.Produce 92.9mg (49%) 2-phenyl-3-(4-Phenylpiperidine-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：424[M+H]+

Step 2.2-phenyl-3-(4-Phenylpiperidine-1-yl) quinoxaline-6-carboxylic acid

To be dissolved in 2-phenyl-3-(4-Phenylpiperidine-1-yl) quinoxaline-6-carboxylate methyl ester (92.9mg of methyl alcohol (15mL); 0.22mmol; 1.00 equivalent) sodium hydroxide of solution and water-soluble (1.5mL) (44mg, 1.10mmol, 5.00 equivalents) solution adds in the 50mL round-bottomed flask.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.With methanol wash gained mixture.Produce 85mg (93%) 2-phenyl-3-(4-Phenylpiperidine-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：410[M+H]+

¹H-NMR(300MHz，DMSO，ppm)：δ13.291(1H，s)，8.311(1H，s)，8.041-7.942(4H，m)，7.611-7.503(3H，m)，7.336-7.179(5H，m)，3.903，3.861(2H，d，J＝12.6Hz)，2.918-2.844(2H，t)，2.708-2.676(1H，t)，1.733-1.628(4H，m)

Embodiment 14

3-(azepan-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(azepan-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents), HMI (87.27mg; 0.88mmol, 2.00 equivalents), DIEA (170.3mg, 1.32mmol; 3.00 equivalent) and N, dinethylformamide (4mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Leach solid.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 100) residue is put on silicagel column.Produce 132.4mg (81%) 3-(azepan-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：362[M+H]+

Step 2.3-(azepan-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in 3-(azepan-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (132.4mg of methyl alcohol (15mL); 0.37mmol; 1.00 equivalent) sodium hydroxide of solution and water-soluble (2mL) (73.4mg, 1.83mmol, 5.00 equivalents) solution adds in the 50mL round-bottomed flask.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.With methanol wash gained mixture.Produce 80mg (61%) 3-(azepan-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：347[M+H]+

¹H-NMR(300MHz，DMSO，ppm)：δ13.204(1H，s)，8.233(1H，s)，7.939-7.873(2H，m)，7.743-7.712(2H，m)，7.565-7.493(3H，m)，3.446-3.408(4H，t)，1.624(4H，s)，1.407(4H，s).

Embodiment 15

3-(4-(4-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(4-(4-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg; 0.44mmol, 1.00 equivalents), 4-(4-chloro-phenyl-) piperidine hydrochlorate (204.2mg, 0.88mmol; 2.00 DIEA (170.3mg equivalent); 1.32mmol, 3.00 equivalents) and N, dinethylformamide (4mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Then through adding the shrend reaction of going out.The solution that obtains is used the 6x15mL dichloromethane extraction, merges organic layer and uses anhydrous sodium sulfate drying.Leach solid.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 146.2mg (71%) 3-(4-(4-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：458[M+H]+

Step 2.3-(4-(4-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in MeOH/THF (1: 1) 3-(4-(4-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (146.2mg (16mL); 0.32mmol; 1.00 the sodium hydroxide (64mg of solution, water-soluble (1.5mL) equivalent); 1.60mmol, 5.00 equivalents) and solution adds in the 50mL round-bottomed flask.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.With methanol wash gained mixture.Solid is dissolved in DMF and carries out the preparation HPLC purifying.Produce 49mg (35%) 3-(4-(4-chloro-phenyl-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：444[M+H]+

¹H-NMR(300MHz，DMSO，ppm)：δ13.264(1H，s)，8.313(1H，s)，8.046-8.004(4H，t)，7.586-7.530(3H，t)，7.377-7.280(4H，m)，3.902，3.861(2H，d，J＝12.3Hz)，2.916-2.842(3H，t)，2.514(1H，s)，1.721-1.644(4H，t).

Embodiment 16

3-morpholino-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-morpholino-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in N, 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, the 0.44mmol of dinethylformamide (4mL); 1.00 equivalent) solution, morpholine (76.6mg, 0.88mmol, 2.00 equivalents), DIEA (170.3mg; 1.32mmol, 3.00 equivalents) add in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Vacuum concentration gained solution.With ethyl acetate/petroleum ether (1: 10) residue is put on silicagel column.Produce 136.4mg (86%) 3-morpholino-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：350[M+H] ⁺

Step 2.3-morpholino-2-phenyl quinoxaline-6-carboxylic acid

Sodium hydroxide (78.2mg, 1.96mmol, the 5.00 equivalents) solution that will be dissolved in 3-morpholino-2-phenyl quinoxaline-6-carboxylate methyl ester (136.4mg, 0.39mmol, 1.00 equivalents) solution of methyl alcohol (12mL), water-soluble (2mL) adds in the 50mL round-bottomed flask.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.The gained mixture carries out preparation HPLC.Produce 56mg (41%) 3-morpholino-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：336[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.323(s，1H)，8.026-7.995(m，4H)，7.609-7.537(m，3H)，3.652-3.622(t，J＝9Hz，4H)，3.247-3.233(d，J＝4.2Hz，4H).

Embodiment 17

3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in N, 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, the 0.44mmol of dinethylformamide (4mL); 1.00 equivalent) solution, 1-methyl isophthalic acid; 4-Diazesuberane (100.3mg, 0.88mmol, 2.00 equivalents), DIEA (170.3mg; 1.32mmol, 3.00 equivalents) add in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Vacuum concentration gained solution.With methylene chloride (20: 1) residue is put on silicagel column.Produce 126.6mg (77%) 3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS：(ES，m/z)：377[M+H] ⁺

Step 2.3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in 3-(the 4-methyl isophthalic acid of methyl alcohol (12mL); 4-Diazesuberane-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (126.6mg; 0.34mmol; 1.00 equivalent) sodium hydroxide of solution, water-soluble (2.5mL) (72.6mg, 1.81mmol, 5.00 equivalents) solution adds in the 50mL round-bottomed flask.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.The gained mixture carries out preparation HPLC.Produce 46mg (38%) 3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：363[M+H] ⁺

¹H?NMR(300MHz，CD ₃OD，ppm)：δ8.470-8.465(d，J＝1.5Hz，1H)，8.102-8.068(m，1H)，7.994-7.965(d，J＝8.7Hz，1H)，7.807-7.776(m，2H)，7.588-7.523(m，2H)，3.620(s，2H)，3.250-3.177(m，2H)，2.906(s，3H)，2.069(s，2H)，1.338-1.289(t，J＝14.7Hz，4H).

Embodiment 18

3-(isopropylamino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(isopropylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in N, 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (100mg, the 0.29mmol of dinethylformamide (4mL); 1.00 equivalent, 99%) solution, third-2-amine (34.5mg, 0.58mmol; 2.00 equivalent), DIEA (112.23mg, 0.87mmol, 3.00 equivalents) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 95.6mg (100%) 3-(isopropylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：322[M+H] ⁺

Step 2.3-(isopropylamino)-2-phenyl quinoxaline-6-carboxylic acid

3-(isopropylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester (95.6mg, 0.30mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (19mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (60mg, 1.50mmol, the 5.00 equivalents) solution that adds water-soluble (3mL) then.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.Crude product is carried out preparation HPLC to obtain product.Produce 55mg (58%) 3-(isopropylamino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：308[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：8.624(s，1H)，8.091-8.057(m，2H)，7.881-7.550(m，3H)，7.678-7.601(m，3H)，5.283(s，1H)，4.541-4.521(d，J＝6Hz，1H)，1.333-1.312(d，J＝6.3Hz，6H).

Embodiment 19

2-phenyl-3-(4-(pyrimidine-2-base) piperazine-1-yl) quinoxaline-6-carboxylic acid

Step 1.2-phenyl-3-(4-(pyrimidine-2-base) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents), 2-(piperazine-1-yl) pyrimidine (144.3mg; 0.88mmol, 2.00 equivalents), DIEA (170.3mg, 1.32mmol; 3.00 equivalent) and N, dinethylformamide (3mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Vacuum concentration gained solution.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 192mg (95%) 2-phenyl-3-(4-(pyrimidine-2-base) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：427[M+H] ⁺

Step 2.2-phenyl-3-(4-(pyrimidine-2-base) piperazine-1-yl) quinoxaline-6-carboxylic acid

To be dissolved in 2-phenyl-3-(4-(pyrimidine-2-base) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester (192mg of methyl alcohol (10mL); 0.41mmol, 1.00 equivalents, 90%) and the sodium hydroxide (80mg of solution and water-soluble (2mL); 2.00mmol, 5.00 equivalents) and solution adds in the 50mL round-bottomed flask.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With methanol wash gained mixture.Produce 80mg (47%) 2-phenyl-3-(4-(pyrimidine-2-base) piperazine-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：413[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.275(s，1H)，8.389-8.336(t，3H)，8.062-8.026(t，4H)，7.609-7.571(t，3H)，6.685-6.654(t，1H)，3.774(s，4H).

Embodiment 20

2-phenyl-3-(4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid

Step 1.2-phenyl-3-(4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg; 0.44mmol, 1.00 equivalents), 1-(5-(trifluoromethyl) pyridine-2-yl) piperazine (203.28mg, 0.88mmol; 2.00 DIEA (170.3mg equivalent); 1.32mmol, 3.00 equivalents) and N, dinethylformamide (3mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Then through adding the shrend reaction of going out.The solution that obtains is used the 4x30mL dichloromethane extraction, merges organic layer and uses anhydrous sodium sulfate drying.Leach solid.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 210.8mg (97%) 2-phenyl-3-(4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：494[M+H] ⁺

Step 2.2-phenyl-3-(4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid

2-phenyl-3-(4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester (210.8mg, 0.43mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (85.5mg, 2.14mmol, the 5.00 equivalents) solution that adds water-soluble (1.5mL) then.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrochloric acid that the pH regulator of this solution is 3-4.This mixture of vacuum concentration.With methanol wash gained mixture.Produce 78mg (38%) 2-phenyl-3-(4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：480[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.310(s，1H)，8.425-8.337(d，J＝26.4Hz，2H)，8.026(s，4H)，7.829-7.800(d，J＝8.7Hz，1H)，7.589-7.570(d，J＝5.7Hz，3H，)6.993-6.963(d，J＝9Hz，1H)，3.694(s，4H)，3.372(s，4H).

Embodiment 21

2-phenyl-3-(4-(quinoline-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid

Step 1.2-phenyl-3-(4-(quinoline-2-yl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg; 0.44mmol, 1.00 equivalents), 3-(piperazine-1-yl) isoquinoline 99.9 dihydrochloride (250.8mg, 0.88mmol; 2.00 DIEA (170.3mg equivalent); 1.32mmol, 3.00 equivalents) and N, dinethylformamide (3mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Then through adding the shrend reaction of going out.The solution that obtains is used the 4x30mL dichloromethane extraction, merges organic layer and uses anhydrous sodium sulfate drying.Leach solid.This mixture of vacuum concentration.With ethyl acetate/petroleum ether (1: 10) residue is put on silicagel column.Produce 216.6mg (rough) 3-(4-(isoquinoline 99.9-3-yl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS(ES，m/z)：476[M+H] ⁺

Step 2.3-(4-(isoquinoline 99.9-3-yl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

3-(4-(isoquinoline 99.9-3-yl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (216.6mg, 0.46mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (91.2mg, 2.28mmol, the 5.00 equivalents) solution that adds water-soluble (2mL) then.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrochloric acid that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.With methanol wash gained mixture.Produce 56mg (26%) 3-(4-(isoquinoline 99.9-3-yl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid like this.

LC-MS：(ES，m/z)：462[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：13.290(s，1H)，8.351(s，1H)，8.073-8.031(m，5H)，7.729-7.703(d，J＝7.8Hz，1H)，7.603-7.513(m，5H)，7.284-7.223(m，2H)，3.755(s，4H)，3.411(s，4H).

Embodiment 22

2-(azepan-1-yl)-3-phenyl quinoxaline-6-carboxylic acid

Step 1.2-(azepan-1-yl)-3-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in N, 2-bromo-3-phenyl quinoxaline-6-carboxylate methyl ester (150mg, the 0.44mmol of dinethylformamide (4mL); 1.00 equivalent) solution, HMI (87.27mg, 0.88mmol, 2.00 equivalents), DIEA (170.3mg; 1.32mmol, 3.00 equivalents) add in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 136mg (84%) 2-(azepan-1-yl)-3-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：362[M+H] ⁺

Step 2.2-(azepan-1-yl)-3-phenyl quinoxaline-6-carboxylic acid

2-(azepan-1-yl)-3-phenyl quinoxaline-6-carboxylate methyl ester (136mg, 0.37mmol, 1.00 equivalents, 98%) solution, the sodium hydroxide (75.3mg, 1.88mmol, 5.00 equivalents) that will be dissolved in methyl alcohol (10mL) add in the 50mL round-bottomed flask.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.With methanol wash gained mixture.Produce 63.1mg (47%) 2-(azepan-1-yl)-3-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：348[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：12.992(s，1H)，8.376-8.371(d，J＝1.5Hz，1H)，8.093-8.058(m，1H)，7.723-7.694(t，J＝8.7Hz，3H)，7.556-7.487(m，3H)，3.467-3.428(t，J＝12.7Hz，4H)，1.621(s，4H)，1.404(s，4H).

Embodiment 23

3-phenyl-2-(piperidines-1-yl) quinoxaline-6-carboxylic acid

Synthesizing of step 1.3-phenyl-2-(piperidines-1-yl) quinoxaline-6-carboxylate methyl ester

To be dissolved in N, 2-bromo-3-phenyl quinoxaline-6-carboxylate methyl ester (150mg, the 0.44mmol of dinethylformamide (4mL); 1.00 equivalent) solution, piperidines (74.8mg, 0.88mmol, 2.00 equivalents), DIEA (170.3mg; 1.32mmol, 3.00 equivalents) add in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.With ethyl acetate/petroleum ether (1: 10) residue is put on silicagel column.Produce 170.9mg (rough) 3-phenyl-2-(piperidines-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：348[M+H] ⁺

Step 2.3-phenyl-2-(piperidines-1-yl) quinoxaline-6-carboxylic acid

3-phenyl-2-(piperidines-1-yl) quinoxaline-6-carboxylate methyl ester (170.9mg, 0.49mmol, 1.00 equivalents) solution, the sodium hydroxide (98.5mg, 2.46mmol, 5.00 equivalents) that will be dissolved in methyl alcohol (12mL) add in the 50mL round-bottomed flask.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.With methanol wash gained mixture.Produce 86mg (52%) 3-phenyl-2-(piperidines-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：334[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：13.034(s，1H)，8.419-8.414(d，J＝1.5Hz，1H)，8.131-8.096(m，1H)，7.955-7.934(s，J＝6.3Hz，1H)，7.796-7.767(s，J＝8.7Hz，1H)，7.585-7.490(m，3H)，1.530(s，6H).

Embodiment 24

2-(4-(4-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylic acid

Step 1.2-(4-(4-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester

To be dissolved in N; 2-chloro-3-(4-fluorophenyl) quinoxaline of dinethylformamide (5mL)-6-carboxylate methyl ester (150mg, 0.47mmol, 1.00 equivalents) solution, 4-(4-chloro-phenyl-) piperidine hydrochlorate (219mg; 0.94mmol; 2.00 equivalent), salt of wormwood (326mg, 2.36mmol, 5.00 equivalents) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Then through adding the 20mL shrend reaction of going out.Gained solution is with methylene chloride (10: 1) extraction and merge organic layer.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 10) residue is put on silicagel column.Produce 200mg (89%) 2-(4-(4-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：476[M+H] ⁺

Step 2.2-(4-(4-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylic acid

2-(4-(4-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester (200mg, 0.42mmol, 1.00 equivalents) solution, the sodium hydroxide (84mg, 2.10mmol, 5.00 equivalents) that will be dissolved in methyl alcohol (30mL) add in the 100mL round-bottomed flask.Gained solution stirred 130 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Gained solution dilutes with 30mL water.Using 1N hydrochloric acid is 3 with the pH regulator of this solution.Solid collected by filtration.This solid decompression is dry in baking oven down.Produce 110mg (57%) 2-(4-(4-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：462[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：13.119(s，1H)，8.430(s，1H)，8.142-8.051(m，3H)，7.821-7.793(d，J＝8.4Hz，1H)，7.437-7.281(m，6H)，3.923-3.88(m，2H)，2.934-2.742(m，3H)，1.732-1.645(m，4H).

Embodiment 25

2-(4-(3-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylic acid

Step 1.2-(4-(3-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester (200mg; 0.63mmol, 1.00 equivalents), 4-(3-chloro-phenyl-) piperidine hydrochlorate (292.4mg, 1.27mmol; 2.00 salt of wormwood (436.7mg equivalent); 3.16mmol, 5.00 equivalents), N, dinethylformamide (4mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.With ethyl acetate/petroleum ether (1: 10) residue is put on silicagel column.Produce 137mg (43%) 2-(4-(3-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：476[M+H] ⁺

Step 2.2-(4-(3-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylic acid

2-(4-(3-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester (137.2mg, 0.28mmol, 1.00 equivalents, the 98%) solution that will be dissolved in methyl alcohol (20mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (57.8mg, 1.45mmol, the 5.00 equivalents) solution that adds water-soluble (2mL) then.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrochloric acid that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.With methanol wash gained mixture.Produce 43mg (33%) 2-(4-(3-chloro-phenyl-) piperidines-1-yl)-3-(4-fluorophenyl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：462[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：8.432(s，1H)，8.428-8.055(m，3H)，7.808-7.779(d，J＝8.7Hz，1H)，7.439-7.230(m，6H)，3.914-3.871(d，J＝12.9Hz，2H)，2.918-2.844(m，2H)，2.791-2.716(t，J＝22.5Hz，1H)，1.751-1.631(m，4H).

Embodiment 26

3-(4-fluorophenyl)-2-(4-(4-p-methoxy-phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid

Step 1.3-(4-fluorophenyl)-2-(4-(4-p-methoxy-phenyl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester (200mg; 0.63mmol, 1.00 equivalents), 4-(4-p-methoxy-phenyl) piperidines (138mg, 0.72mmol; 2.00 salt of wormwood (436.7mg equivalent); 3.16mmol, 5.00 equivalents), N, dinethylformamide (4mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.With ethyl acetate/petroleum ether (1: 10) residue is put on silicagel column.Produce 123.9mg (37%) 3-(4-fluorophenyl)-2-(4-(4-p-methoxy-phenyl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：472[M+H] ⁺

Step 2.3-(4-fluorophenyl)-2-(4-(4-p-methoxy-phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid

3-(4-fluorophenyl)-2-(4-(4-p-methoxy-phenyl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester (123.9mg, 0.24mmol, 1.00 equivalents, 93%) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (52.6mg, 1.31mmol, the 5.00 equivalents) solution that adds water-soluble (3mL) then.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrochloric acid that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.With methanol wash gained mixture.Produce 60mg (52%) 3-(4-fluorophenyl)-2-(4-(4-p-methoxy-phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：458[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：8.794-8.789(d，J＝1.5Hz，1H)，8.309-8.274(m，1H)，8.085-8.038(m，2H)，7.900-7.871(d，J＝8.7Hz，1H)，7.273-7.155(m，4H)，6.905-6.877(d，J＝8.4Hz，2H)，4.079-4.035(d，J＝13.2Hz，2H)，2.988-2.909(t，J＝23.7Hz，2H)，2.733-2.656(t，J＝23.1Hz，1H)，1.899-1.684(m，4H).

Embodiment 27

3-(4-fluorophenyl)-2-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid

Step 1.3-(4-fluorophenyl)-2-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester (200mg; 0.63mmol, 1.00 equivalents), 1-(pyridine-2-yl) piperazine (207mg, 1.27mmol; 2.00 salt of wormwood (436.7mg equivalent); 3.16mmol, 5.00 equivalents), N, dinethylformamide (4mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Then through adding the shrend reaction of going out.Gained solution is with the 5x50mL dichloromethane extraction and merge organic layer.This mixture of vacuum concentration.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 157.4mg (56%) 3-(4-fluorophenyl)-2-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：444[M+H] ⁺

Step 2.3-(4-fluorophenyl)-2-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid

3-(4-fluorophenyl)-2-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylate methyl ester (157.4mg, 0.36mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (71.1mg, 1.78mmol, the 5.00 equivalents) solution that adds water-soluble (2mL) then.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrochloric acid that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.With methanol wash gained mixture.Produce 36mg (23%) 3-(4-fluorophenyl)-2-(4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：430[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.468-8.463(d，J＝1.5Hz，1H)，8.180-8.146(m，3H)，8.099-8.053(t，1H)，7.874-7.794(t，1H)，7.448-7.389(t，2H)，7.140(s，1H)，6.833(s，1H)，3.670(s，4H)，3.452(s，4H).

Embodiment 28

2-phenyl-3-(4-(3-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid

Step 1.4-(3-(trifluoromethyl) pyridine-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester

With 2-chloro-3-(trifluoromethyl) pyridine (500mg, 2.76mmol, 1.00 equivalents), 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (1.705g, 5.52mmol, 2.00 equivalents), PCy ₃(216.4mg, 0.77mmol, 0.28 equivalent), Pd ₂(dba) ₃(304.7mg, 0.33mmol, 0.12 equivalent), NaOt-Bu (828mg, 8.28mmol, 3.00 equivalents), two

Alkane (8mL) adds in the 20mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With PE/EA (10: 1) residue is put on silicagel column.Produce 449.3mg (46%) 4-(3-(trifluoromethyl) pyridine-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester yellow oil.

LC-MS：(ES，m/z)：329[M+H] ⁺

Step 2.4-(3-(trifluoromethyl) pyridine-2-yl) piperidines-1-carboxylic acid tert-butyl ester

To be dissolved in the 4-(3-(trifluoromethyl) pyridine-2-yl)-5 of methyl alcohol (20mL); 6-dihydropyridine-1 (the 2H)-carboxylic acid tertiary butyl (449.3mg; 1.27mmol, 1.00 equivalents, 93%) and solution and anhydrous palladium carbon (134.8mg) adds with in hydrogen inert atmosphere purging and the 50-mL round-bottomed flask kept.Gained solution is stirred overnight at room temperature.Leach solid.The mixture of vacuum concentration gained.Produce 379.8mg (87%) 4-(3-(trifluoromethyl) pyridine-2-yl) piperidines-1-carboxylic acid tert-butyl ester water white oil.

LC-MS：(ES，m/z)：331[M+H] ⁺

Step 3.2-(piperidin-4-yl)-3-(trifluoromethyl) pyridine

4-(3-(trifluoromethyl) pyridine-2-yl) piperidines-1-carboxylic acid tert-butyl ester (379.8mg, 1.10mmol, 1.00 equivalents, the 96%) solution that will be dissolved in methylene dichloride (10mL) adds in the 50mL round-bottomed flask.0 ℃ is dropwise stirred adding trifluoroacetic acid (5mL) then.Stirring at room gained solution 3 hours.Use saturated sodium bicarbonate that the pH regulator of this solution is 8-9.The solution that obtains is used the 6x50mL dichloromethane extraction, merges organic layer and uses anhydrous sodium sulfate drying.Leach solid.The mixture of vacuum concentration gained.Produce 237.4mg (93%) 2-(piperidin-4-yl)-3-(trifluoromethyl) pyridine yellow oil.

LC-MS：(ES，m/z)：231[M+H] ⁺

Step 4.2-phenyl-3-(4-(3-(trifluoromethyl) pyridine-2-yl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (176.5mg; 0.52mmol, 1.00 equivalents), 2-(piperidin-4-yl)-3-(trifluoromethyl) pyridine (237.4mg, 1.03mmol; 2.00 salt of wormwood (356.1mg equivalent); 2.58mmol, 5.00 equivalents) and N, dinethylformamide (4mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 236.2mg (87%) 2-phenyl-3-(4-(3-(trifluoromethyl) pyridine-2-yl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS：(ES，m/z)：493[M+H] ⁺

Step 5.2-phenyl-3-(4-(3-(trifluoromethyl) pyridine-2-yl) piperidines-1-yl) quinoxaline-6-carboxylic acid

2-phenyl-3-(4-(3-(trifluoromethyl) pyridine-2-yl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester (236.2mg, 0.46mmol, 1.00 equivalents, 95%) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (91.2mg, the 5.00 equivalents) solution that adds water-soluble (2mL) then.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Use 1N hydrochloric acid that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.With methanol wash gained mixture.Produce 105.4mg (48%) 2-phenyl-3-(4-(3-(trifluoromethyl) pyridine-2-yl) piperidines-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：479[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：13.201(s，1H)，8.848-8.834(d，J＝4.2Hz，1H)，8.316(s，1H)，8.135-8.111(d，J＝7.2Hz，1H)，8.028-8.010(d，J＝5.4Hz，4H)，7.605-7.455(m，4H)，3.947-3.904(d，J＝12.9Hz，2H)，3.186-3.147(m，1H)，2.946-3.881(t，J＝12.3Hz，2H)，2.083-1.966(dd，J＝12.6Hz，2H)，1.668-1.631(d，J＝11.1Hz，2H).

Embodiment 29

3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid

Step 1.3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester

To be dissolved in N; The 4-of dinethylformamide (10mL) (4-(trifluoromethyl) phenyl) piperidines (420mg, 1.83mmol, 3.00 equivalents), 2-chloro-3-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester (150mg; 0.47mmol; 1.00 equivalent), DIEA (305mg, 2.36mmol, 5.00 equivalents) solution adds in the 20-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 10) residue is put on silicagel column.Produce 200mg (83%) 3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：510[M+H] ⁺

Step 2.3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid

To be dissolved in 3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester (120mg of methyl alcohol (20mL); 0.24mmol; 1.00 the sodium hydroxide (47.2mg of solution and water-soluble (2mL) equivalent); 1.18mmol, 5.00 equivalents) and solution adds in the 50mL round-bottomed flask.Gained solution stirred 3 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Gained solution dilutes with 30mL water.Using 1N hydrochloric acid is 3 with the pH regulator of this aqueous solution.Solid collected by filtration, and with the water washing of 10mLx1.This solid decompression is dry in baking oven down.This solid of recrystallization purifying from methyl alcohol.Produce 60mg (51%) 3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl) phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：496[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：13.105(s，1H)，8.447(s，1H)，8.158-8.072(m，3H)，7.841-7.812(m，1H)，7.608-7.558(m，4H)，7.449-7.391(m，2H)，3.962-3.920(m，2H)，2.971-2.888(m，3H)，1.800-1.723(m，4H).

Embodiment 30

2, two (4-Phenylpiperidine-1-yl) quinoxalines-6-carboxylic acid of 3-

Step 1.2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid, ethyl ester

To be dissolved in 3 of oxalic acid diethyl ester (100mL), 4-2-aminobenzoic acid ethyl ester (5g, 27.75mmol, 1.00 equivalents) solution places the 250-mL round-bottomed flask.Stirred overnight in 140 ℃ of oil baths of gained solution.Gained solution is reduced to room temperature then.Solid collected by filtration.This solid decompression is dry in baking oven down.Produce 3.5g (54%) 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid, ethyl ester brown solid.

Step 2.2,3-dichloro-quinoxaline-6-carboxylic acid, ethyl ester

To be dissolved in 2 of toluene (100mL), 3-dioxo-1,2; 3,4-tetrahydroquinoxaline-6-carboxylic acid, ethyl ester (3.7g, 15.80mmol; 1.00 equivalent) solution and THIONYL CHLORIDE 97 (37.6g, 315.97mmol, 20.00 equivalents), N; Dinethylformamide (2.75g, 31.61mmol, 2.00 equivalents) adds in the 250mL round-bottomed flask.Gained solution reflux 3 hours in oil bath.The mixture of vacuum concentration gained.The gained mixture cleans with 100mL ether.Produce 2.5g (58%) 2,3-dichloro-quinoxaline-6-carboxylic acid, ethyl ester brown solid.

LC-MS：(ES，m/z)：271[M+H] ⁺

Step 3.2, two (4-Phenylpiperidine-1-yl) quinoxalines-6-carboxylic acid, ethyl ester of 3-

To be dissolved in N, 2 of dinethylformamide (10mL), 3-dichloro-quinoxaline-6-carboxylic acid, ethyl ester (150mg; 0.55mmol, 1.00 equivalents), 4-Phenylpiperidine (298mg, 1.85mmol; 3.00 equivalent), DIEA (398mg, 3.09mmol, 5.00 equivalents) solution adds in the 20-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 10) residue is put on silicagel column.Produce two (4-Phenylpiperidine-1-yl) quinoxalines of 180mg (62%) 2,3--6-carboxylic acid, ethyl ester yellow solid.

LC-MS：(ES，m/z)：521[M+H] ⁺

Step 4.2, two (4-Phenylpiperidine-1-yl) quinoxalines-6-carboxylic acid of 3-

To be dissolved in 2 of methyl alcohol (25mL), sodium hydroxide (58mg, 1.45mmol, the 5.00 equivalents) solution of two (4-Phenylpiperidine-1-yl) quinoxaline-6-carboxylic acid, ethyl ester (150mg, 0.29mmol, the 1.00 equivalents) solution of 3-and water-soluble (2mL) adds in the 50mL round-bottomed flask.Gained solution stirred 3 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Gained solution dilutes with 30mL water.Using 1N hydrochloric acid is 3 with the pH regulator of this aqueous solution.Filter and collect the gained solid.This solid decompression is dry also through recrystallization purifying from methyl alcohol in baking oven down.Produce two (4-Phenylpiperidine-1-yl) quinoxalines of 80mg (56%) 2,3--6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：493[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：12.952(s，1H)，8.172(s，1H)，7.915-7.883(d，J＝9.6Hz，1H)，7.662-7.634(d，J＝8.4Hz，1H)，7.292-7.197(m，10H)，4.605-4.426(m，4H)，3.072-2.831(m，6H)，1.830-1.791(m，8H).

Embodiment 31

2, two (4-p-methoxy-phenyl)-6-(1H-tetrazolium-5-yl) quinoxalines of 3-

Step 1.2, two (4-p-methoxy-phenyl) quinoxalines of 3--6-nitrile

To be dissolved in 1 of acetate (20mL), two (4-p-methoxy-phenyl) ethane-1 of 2-, 2-diketone (200mg, 0.74mmol, 1.00 equivalents) solution, 3,4-diamino-benzonitrile (118.2mg, 0.89mmol, 1.20 equivalents) adds in the 100mL round-bottomed flask.Oil bath was stirred 1 hour under gained solution refluxed.Then through adding the shrend reaction of going out.Solid collected by filtration is also washed with MeOH.Produce two (4-p-methoxy-phenyl) quinoxalines of 205mg (71%) 2,3--6-nitrile yellow solid.

LC-MS-PH：(ES，m/z)：368[M+H]+

Step 2.2, two (4-p-methoxy-phenyl)-6-(1H-tetrazolium-5-yl) quinoxalines of 3-

To be dissolved in N, 2 of dinethylformamide (7mL), two (4-p-methoxy-phenyl) quinoxalines of 3--6-nitrile (200mg, 0.51mmol; 1.00 equivalent, 93%) solution, NaN3 (500mg, 7.69mmol; 15.18 equivalent), NH4Cl (147.9mg, 2.79mmol, 5.00 equivalents) adds in the 20-mL ST.Gained solution stirred 4 hours in 100 ℃ of oil baths.Then through adding the shrend reaction of going out.The solution that obtains merges organic layer and uses anhydrous sodium sulfate drying with 8x50mL methylene dichloride/MeOH (10: 1) extraction.Leach solid.The mixture of vacuum concentration gained.With methanol wash gained mixture.Produce two (4-p-methoxy-phenyl)-6-(1H-tetrazolium-5-yl) the quinoxaline yellow solids of 47mg (23%) 2,3-.

LC-MS：(ES，m/z)：411[M+H]+

¹H-NMR(300MHz，DMSO，ppm)：δ8.760(1H，s)，8.463-8.293(4H，m)，7.523，7.498(4H，d，J＝7.5Hz)，6.995，6.971(4H，d，J＝7.2Hz)，3.861(6H，s).

Embodiment 32

3-(4-(N-methylmethane-3-ylsulfonylamino) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(4-(N-methylmethane-3-ylsulfonylamino) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in 3-(4-(methylamino) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (215mg of methylene dichloride (14mL); 0.57mmol; 1.00 equivalent) solution, methylsulfonyl chloride (71.7mg, 0.63mmol, 1.10 equivalents) and triethylamine (287.85mg; 2.85mmol, 5.00 equivalents) add in the 50mL round-bottomed flask.Stirring at room gained solution 3 hours.Then through adding saturated sodium bicarbonate cancellation reaction.Vacuum concentration gained solution.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 293.5mg (rough) 3-(4-(N-methylmethane-3-ylsulfonylamino) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS(ES，m/z)：455[M+H] ⁺

Step 2.3-(4-(N-methylmethane-3-ylsulfonylamino) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

3-(4-(N-methylmethane-3-ylsulfonylamino) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (293.5mg, 0.60mmol, 1.00 equivalents, 93%) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (129.3mg, 3.23mmol, the 5.00 equivalents) solution that adds water-soluble (3mL) then.Gained solution is stirred overnight in 50 ℃ of oil baths.Use the 1N hydrochloride aqueous solution that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.With methyl alcohol and water washing gained solid, filter and drying under vacuum.Produce 78mg (29%) 3-(4-(N-methylmethane-3-ylsulfonylamino) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：441[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.306(s，1H)，8.001-7.986(d，J＝4.5Hz，4H)，7.587-7.563(d，J＝7.2Hz，3H)，3.858-3.774(t，J＝12.6Hz，3H)，2.905-2.805(m，5H)，2.702(s，3H)，1.764-1.696(t，J＝10.2Hz，2H)，1.614-1.580(d，J＝10.2Hz，2H).

Embodiment 33

3-(4-(methylsulfonyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(4-(methylsulfonyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

2-phenyl-3-(piperazine-1-yl) quinoxaline-6-carboxylate methyl ester (150mg, 0.43mmol, 1.00 equivalents), DIEA (3mL) solution that will be dissolved in DCM (15mL) add in the 100mL round-bottomed flask.0 ℃ adds methylsulfonyl chloride (0.5mL) then.Gained solution is stirred overnight at room temperature.With saturated NaCl cleaning reaction and vacuum concentration.Produce 0.17g (93%) 3-(4-(methylsulfonyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester palm fibre yellow oil.

Step 2.3-(4-(methylsulfonyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid:

3-(4-(methylsulfonyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (170mg, 0.40mmol, 1.00 equivalents), methyl alcohol (15mL) solution that will be dissolved in methylene dichloride (5mL) add in the 100mL round-bottomed flask.Sodium hydroxide (190mg, 4.75mmol, the 11.90 equivalents) solution that adds water-soluble (10mL) then.Stirring at room gained solution 3 hours.Gained mixture vacuum concentration also dilutes with 10ml water.Using hydrochloric acid is 3 with the pH regulator of this aqueous solution.Filter and collect the gained solid.Produce 20mg (12%) 3-(4-(methylsulfonyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid brown solid.

LC-MS(ES，m/z)：413[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.29(s，1H)，8.35-7.57(m，8H)，3.18(m，4H)，2.92(s，3H).

Embodiment 34

3-(4-(N-methyl kharophen) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(4-(tert-butoxycarbonyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid:

3-(4-(tert-butoxycarbonyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (700mg, 1.52mmol, 1.00 equivalents) solution that will be dissolved in THF (50mL) adds in the 100mL round-bottomed flask.Add sodium hydroxide (300mg, 12.50mmol, 8.25 equivalents) then.Gained mixture stirring at room 1 hour.To the CH that wherein adds 0 ℃ ₃I (0.5mL).Stirring at room gained solution 3 hours.Then through adding frozen water cancellation reaction.The mixture of vacuum concentration gained.Produce 0.65g (93%) 3-(4-(tert-butoxycarbonyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow oil.

Step 2.3-(4-(tert-butoxycarbonyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in N; The 3-of dinethylformamide (15mL) (4-(tert-butoxycarbonyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid (509.7mg; 1.10mmol; 1.00 equivalent) solution, salt of wormwood (762.3mg, 5.52mmol, 5.00 equivalents) add in the 100mL round-bottomed flask that purges and keep with the nitrogen inert atmosphere.Gained solution at room temperature stirred 30 minutes.0 ℃ is dropwise stirred adding CH then ₃I (783.3mg, 5.52mmol, 5.00 equivalents).Stirring at room gained solution 3 hours.Then through adding the shrend reaction of going out.The aqueous solution that obtains is with the dichloromethane extraction of 6x20mL.Merge organic layer, with anhydrous sodium sulfate drying and vacuum concentration.Produce 285.5mg (54%) 3-(4-(tert-butoxycarbonyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS(ES，m/z)：477[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：d?8.67-7.51(m，8H)，3.99(s，3H)，3.95(m，1H)，2.74(s，3H)，1.45(s，9H).

Step 3.3-(4-(methylamino-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

3-(4-(tert-butoxycarbonyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (360mg, 0.60mmol, 1.00 equivalents, 79%) solution that will be dissolved in methylene dichloride (30mL) adds in the 100mL round-bottomed flask.0 ℃ adds trifluoroacetic acid (2mL) then.Gained solution stirring at room 3 hours.Gained solution is with the dilution of 20ml water and use saturated NaHCO ₃Be adjusted to pH9.This aqueous solution is used dichloromethane extraction, merges organic layer and vacuum concentration.Produce 0.20g (89%) 3-(4-(methylamino-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester red-brown oil.

LC-MS(ES，m/z)：377[M+H] ⁺

Step 4.3-(4-(N-methyl kharophen) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester:

3-(4-(methylamino-) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (76mg, 0.20mmol, 1.00 equivalents) solution that will be dissolved in methylene dichloride (15mL) adds in the 100mL round-bottomed flask.Add Et then ₃N (1.25mL).The methylcarbonate (0.75mL) that in above-mentioned solution, adds 0 ℃.Gained solution stirring at room 3 hours.The mixture of vacuum concentration gained.Produce 0.077g (91%) 3-(4-(N-methyl kharophen) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester light yellow oil.

LC-MS(ES，m/z)：419[M+H] ⁺

¹H?NMR(300MHz，DMSO)：δ8.54-7.51(m，8H)，4.01(s，3H)，2.87(s，3H).

Step 5.3-(4-(N-methyl kharophen) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

3-(4-(N-methyl kharophen) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (77mg, 0.18mmol, 1.00 equivalents) solution that will be dissolved in MeOH (15mL) adds in the 100mL round-bottomed flask.Add methylene dichloride (5mL) then.Sodium hydroxide (700mg, 17.50mmol, the 95.00 equivalents) solution that in above-mentioned, adds water-soluble (3mL) subsequently.Gained solution stirring at room 3 hours.Gained mixture vacuum concentration also dilutes with 10ml water.Using the 3N aqueous hydrochloric acid is 3 with the pH regulator of this aqueous solution.Filter and collect the gained solid.Produce 52mg (70%) 3-(4-(N-methyl kharophen) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：405[M+H] ⁺

¹H?NMR(300MHz，DMSO)：δ13.27(s，1H)，8.31-7.54(m，8H)，4.44-4.41(m，1H)，3.87-3.82(m，2H)，2.93-2.67(m，5H)，2.05-1.98(m，3H)，1.78-1.40(m，4H).

Embodiment 35

3-(4-(methyl (phenyl) amino) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.2-phenyl-3-(4-(phenyl amino) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester

3-(4-oxo-piperidine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (329.7mg, 0.91mmol, 1.00 equivalents) solution that will be dissolved in Virahol (12mL) adds in the 100mL round-bottomed flask that purges and keep with the nitrogen inert atmosphere.Dropwise stir then and add aniline (255.2mg, 2.74mmol, 3.00 equivalents) and acetate (221.8mg, 3.70mmol, 4.00 equivalents).Gained solution stirred 1 hour in 60 ℃ of oil baths.The NaHB (OAc) that in above-mentioned, adds 0 ℃ ₃(968.1mg, 4.57mmol, 4.57 equivalents).Extra 3 hours of gained solution stirring at room.Then through adding the shrend reaction of going out.The aqueous solution that obtains is with the dichloromethane extraction of 6x20mL.Merge organic layer, with dried over sodium sulfate and vacuum concentration.With DCM/MeOH (30: 1) residue is put on silicagel column.Produce 297.4mg (74%) 2-phenyl-3-(4-(phenyl amino) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS(ES，m/z)：439[M+H] ⁺

Step 2.3-(4-(methyl (phenyl) amino) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

2-phenyl-3-(4-(phenyl amino) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester (297.4mg, 0.68mmol, 1.00 equivalents) solution that will be dissolved in THF (16mL) adds in the 50mL round-bottomed flask.Add sodium hydride (163mg, 6.79mmol, 10.00 equivalents) and CH ₃I (964mg, 6.79mmol, 10.00 equivalents).Gained solution stirring at room 2 days.Then through adding the shrend reaction of going out.The aqueous solution that obtains is used the 5x30mL dichloromethane extraction.Merge organic layer and vacuum concentration.Through preparation HPLC (Agilent preparation HPLC (UV-guiding)), with following condition purifying crude product (150mg): post, SunFire Prep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 25%CH of CN ₃CN brought up to 60% with 6 minutes, brought up to 100% with 1 minute again); Detector, UV 254nm.Obtain the 30mg product.Produce 30mg (10%) 3-(4-(methyl (phenyl) amino) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：439[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)8.307(s，1H)，8.026-8.001(d，J＝7.5Hz，4H)，7.591-7.539(t，J＝7.8Hz，3H)，7.190-7.138(t，J＝7.8Hz，2H)，6.827-6.800(d，J＝8.1Hz，2H)，6.652-6.603(t，J＝7.35Hz，1H)，3.885-3.845(d，J＝12Hz，4H)，2.965-2.885(t，J＝24Hz，2H)，2.713(s，3H)，1.769-1.736(d，J＝9.9Hz，2H)，1.596-1.561(d，J＝10.5Hz，2H).

Embodiment 36

3-(diethylamino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(diethylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in N, 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, the 0.44mmol of dinethylformamide (3mL); 1.00 equivalent) solution, diethylamine (63.4mg, 0.87mmol, 2.00 equivalents) and DIEA (170.3mg; 1.32mmol, 3.00 equivalents) add in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Vacuum concentration gained solution.Residue is put on silicagel column also with ethyl acetate/petroleum ether (1: 100) wash-out.Produce 117mg (80%) 3-(diethylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS(ES，m/z)：336[M+H] ⁺

Step 2.3-(diethylamino)-2-phenyl quinoxaline-6-carboxylic acid

3-(diethylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester (117mg, 0.35mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (69.9mg, 1.75mmol, the 5.00 equivalents) solution that adds water-soluble (2mL) then.Gained solution is stirred overnight in 50 ℃ of oil baths.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.Through preparation HPLC with following condition purifying crude product (110mg): post, SunFire Prep C18,5um, 19*150mm; Moving phase contains the water (70% methyl alcohol brought up to 90% with 10 minutes) of 0.05%TFA and methyl alcohol; Detector, UV 254nm.Produce 70mg (62%) 3-(diethylamino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：322[M+H] ⁺

¹H?NMR(300MHz，DMSO，ppm)：δ13.24(s，1H)，8.28(s，1H)，7.95(s，2H)，7.85-7.82(t，J＝4.5Hz，2H)，7.58-7.49(m，3H)，3.30-3.28(d，J＝6Hz，4H)，1.04-0.99(t，J＝7.5Hz，6H).

Embodiment 37

3-(4-kharophen piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(4-(tert-butoxycarbonyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (200mg, 0.58mmol, 1.00 equivalents), piperidin-4-yl t-butyl carbamate (300mg; 1.50mmol; 2.58 equivalent), DIEA (300mg, 2.33mmol, 3.00 equivalents) and DMSO (2mL) add in the 8-mL ST.100 ℃ of stirred overnight of the solution that obtains.Gained solution dilutes with ETHYLE ACETATE.Gained solution cleans with saturated sodium-chloride, then vacuum concentration.Produce 0.2g (74%) 3-(4-(tert-butoxycarbonyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester light yellow solid.

Step 2.3-(4-amino piperidine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

3-(4-(tert-butoxycarbonyl) piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.31mmol, 1.00 equivalents, 95%) solution that will be dissolved in methylene dichloride (15mL) adds in the 100mL round-bottomed flask.0 ℃ adds trifluoroacetic acid (2mL) then.Stirring at room gained solution 3 hours.The mixture of vacuum concentration gained.Gained solution dilutes with 10mL water.Using saturated sodium bicarbonate is 8 with the pH regulator of this aqueous solution.The aqueous solution that obtains is used dichloromethane extraction.Merge organic layer and vacuum concentration.Produce 0.06g (53%) 3-(4-amino piperidine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester light yellow solid.

Step 3.3-(4-kharophen piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

3-(4-amino piperidine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (100mg, 0.28mmol, 1.00 equivalents) solution that will be dissolved in methylene dichloride (50mL) adds in the 50mL round-bottomed flask.0 ℃ adds triethylamine (7ml) and diacetyl oxide (1mL) then.The solution stirred overnight at room temperature and the vacuum concentration that obtain.Produce 0.1g (90%) 3-(4-kharophen piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester light yellow oil.

Step 4.3-(4-kharophen piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

3-(4-kharophen piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (100mg, 0.25mmol, 1.00 equivalents), methyl alcohol (15mL), methylene dichloride (7mL) are added in the 100mL round-bottomed flask.Sodium hydroxide (1.5g, 37.50mmol, the 151.50 equivalents) solution that adds water-soluble (7mL) subsequently.Stirring at room gained solution 3 hours.Gained mixture vacuum concentration also dilutes with 10ml water.Using hydrochloric acid is 3 with the pH regulator of this aqueous solution.Filter and collect the gained solid.Produce 95mg (94%) 3-(4-kharophen piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid light yellow solid.

LC-MS(ES，m/z)：391[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.30(m，1H)，7.99-7.98(m，4H)，7.84-7.82(m，1H)，7.56-7.55(m，3H)，3.71-3.61(m，3H)，2.92-2.85(m，2H)，1.78(s，3H)，1.73-1.70(m，2H)，1.46-1.39(m，2H).

Embodiment 38

3-(N-methylmethane-5-ylsulfonylamino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(N-methylmethane-5-ylsulfonylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (200mg, 0.58mmol, 1.00 equivalents), N-methylmethane sulphonamide (381mg, 3.49mmol, 3.00 equivalents), K ₃PO ₄(370mg, 1.75mmol, 3.00 equivalents), CuI (110mg, 0.58mmol, 1.00 equivalents), N1, N1, N2, N2-tetramethyl-ethane-1,2-diamines (67mg, 0.58mmol, 1.00 equivalents), 1,4-two

Alkane (5mL) adds in the 10-mL ST.Gained solution is stirred overnight in 100 ℃ of oil baths.The mixture of vacuum concentration gained.Use PE: EA (20: 1) puts on silicagel column with residue.Produce 110mg (51%) 3-(N-methylmethane-5-ylsulfonylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS(ES，m/z)：372[M+H] ⁺

Step 2.3-(N-methylmethane-5-ylsulfonylamino)-2-phenyl quinoxaline-6-carboxylic acid

With 3-(N-methylmethane-5-ylsulfonylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester (130mg; 0.35mmol; 1.00 equivalent), LiOH (16.8mg, 0.70mmol, 2.00 equivalents), methyl alcohol (10mL), water (2ml), methylene dichloride (2mL) add in the 50mL round-bottomed flask.Gained solution stirred 2 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Gained solution dilutes with 20mL water.Gained solution is with 2x20ml dichloromethane extraction and combining water layer.With hydrochloride aqueous solution (1mol/L) the pH value of this solution is adjusted to 4.Solid collected by filtration.Produce 80mg (63%) 3-(N-methylmethane-5-ylsulfonylamino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：358[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.645(s，1H)，8.366-8.338(d，J＝8.4Hz，1H)，8.266-8.237(d，J＝8.7Hz，1H)，7.944-7.913(m，2H)，7.612-7.577(m，3H)，3.269(s，3H)，3.141(s，3H).

Embodiment 39

3-(3,4-dihydro-isoquinoline-2 (1H)-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(3,4-dihydro-isoquinoline-2 (1H)-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (130mg, 0.38mmol, 1.00 equivalents); N, dinethylformamide (5mL), 1,2; 3,4-tetrahydroisoquinoline (101.1mg, 0.76mmol; 2.00 equivalent), the solution of salt of wormwood (157.3mg, 1.14mmol, 3.00 equivalents) adds in the 8-mL ST.100 ℃ of stirred overnight of the solution that obtains.Then through adding the shrend reaction of going out.Filter and collect the gained solid.Generation 110mg (70%) 3-(3,4-dihydro-isoquinoline-2 (1H)-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：396[M+H] ⁺

Step 2.3-(3,4-dihydro-isoquinoline-2 (1H)-yl)-2-phenyl quinoxaline-6-carboxylic acid

(3,4-dihydro-isoquinoline-2 (1H)-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (110mg, 0.26mmol, 1.00 equivalents, 95%) solution adds in the 50mL round-bottomed flask will to be dissolved in the 3-of methyl alcohol (15mL).Dropwise stir sodium hydroxide (55.7mg, 1.39mmol, the 5.00 equivalents) solution that adds water-soluble (1.5mL) then.Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Vacuum concentration gained solution.The dilute with water residue.Use 1N hydrogenchloride that the pH regulator of this aqueous solution is 3-4.Filter and collect the gained solid and use methanol wash.Generation 68.1mg (66%) 3-(3,4-dihydro-isoquinoline-2 (1H)-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：382[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)8.36(s，1H)，8.00-7.93(m，4H)，7.58-7.55(t，J＝4.5Hz，3H)，7.18-7.14(m，4H)，4.57(s，2H)，3.39-3.36(d，J＝9Hz，2H)，2.72-2.70(d，J＝6Hz，2H).

Embodiment 40

3-(3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1. is synthesized 3-(2-bromophenyl) propionitrile

Acetonitrile (49g, 1.20mol, the 9.96 equivalents) solution that will be dissolved in THF (150mL) adds in the 500mL 3 neck round-bottomed flasks.Dropwise stir in-78 ℃ then and add BuLi (72mL, 1.50 equivalents).-78 ℃ were stirred 1 hour.Dropwise stir 1-bromo-2-(brooethyl) benzene (30g, 120.00mmol, the 1.00 equivalents) solution that adding is dissolved in THF (100mL) in-78 ℃.Gained solution stirred 1 hour in-78 ℃.Add 100mL shrend this reaction of going out in-78 ℃.The aqueous solution that obtains is used the 3x100mL ethyl acetate extraction, merges organic layer and uses anhydrous sodium sulfate drying, vacuum concentration then.With ethyl acetate/petroleum ether (1: 20) residue is put on silicagel column.Collect cut through the decompression thick product of (2mm Hg) distillation purifying and in 98-107 ℃.Produce 3-(2-bromophenyl) the propionitrile water white oil of 13.21g (52%).

GC-MS：(ES，m/z)：209[M] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)7.61-7.58(d，J＝7.8Hz，1H)，7.35-7.29(m，2H)，7.22-7.15(m，1H)，3.15-3.09(t，J＝7.5Hz，2H)，2.73-2.68(t，J＝7.5Hz，2H).

Step 2.3-(2-bromophenyl) third-1-amine

3-(2-bromophenyl) propionitrile (2.1g, 10.00mmol, the 1.00 equivalents) solution that will be dissolved in THF (20mL) adds in the 250mL 3 neck round-bottomed flasks.Dropwise stir in 0 ℃ then and add borine (1mol/L is dissolved in THF, 50mL, 5.00 equivalents).Gained solution stirred overnight at room temperature.0 ℃ is added the 50mL shrend reaction of going out then, and uses the 3x50mL ethyl acetate extraction.Merge organic layer, with anhydrous sodium sulfate drying and vacuum concentration.Residue is dissolved in the 30mL 6N hydrochloride aqueous solution.This aqueous solution is with 30mL ethyl acetate extraction and combining water layer.Using 10% aqueous sodium hydroxide solution is 10 with the pH regulator of the above-mentioned aqueous solution.Gained solution is used the 3x50mL ethyl acetate extraction.Merge organic layer, with anhydrous sodium sulfate drying and vacuum concentration.Produce 3-(2-bromophenyl) third-1-amine water white oil of 1.3g (58%).

LC-MS：(ES，m/z)：214[M+H] ⁺

Step 3.3-(3-(2-bromophenyl) propyl group is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-chloro-2-phenyl quinoxaline-6-carboxylate methyl ester (180mg, 0.60mmol, 1.00 equivalents), toluene/DMSO (5/1mL), 3-(2-bromophenyl) third-1-amine (385mg; 1.80mmol; 2.99 equivalent) and salt of wormwood (414mg, 3.00mmol, 4.98 equivalents) add in the 20-mL ST.100 ℃ of stirred overnight of the solution that obtains.This mixture of vacuum concentration.Through this residue of silica gel column chromatography purifying with ethyl acetate/petroleum ether (1: 50).Produce 240mg (80%) 3-(3-(2-bromophenyl) propyl group is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：476[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ1.99-1.91(m，2H)，2.81-2.75(t，J＝7.8Hz，2H)，3.54-3.47(m，2H)，3.92(s，3H)，6.97-6.93(t，J＝5.4Hz，1H)，7.17-7.11(m，1H)，7.34-7.28(m，1H)，7.43-7.39(dd，J＝1.5，7.6Hz，4H)，7.69-7.54(m，2H)，7.90-7.68(m，2H)，7.15(m，1H).

Step 4.3-(3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in two The 3-of alkane (10mL) (3-(2-bromophenyl) propyl group is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester (240mg, 0.50mmol, 1.00 equivalents) solution, CsCO ₃(490mg, 1.50mmol, 3.00 equivalents), Pd ₂(dba) ₃(46mg, 0.05mmol, 0.10 equivalent) and BINAP (125mg, 0.20mmol, 0.40 equivalent) add in the 20mL ST.100 ℃ of stirred overnight of the solution that obtains.This mixture vacuum concentration also passes through the rapid column chromatography purifying with ethyl acetate/petroleum ether (1: 50).Generation 180mg (86%) 3-(3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：396[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.37(s，1H)，8.10(d，J＝0.9Hz，2H)，7.83-7.77(m，1H)，7.74-7.70(m，2H)，7.49-7.45(m，1H)，7.29-7.26(m，3H)，6.99-6.95(m，1H)，6.74-6.61(m，3H)，3.95(s，1H)，3.76-3.70(t，J＝6.6Hz，2H)，2.75-2.70(t，J＝6.6Hz，2H)，2.03-1.94(m，2H).

Step 5.3-(3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid

With 3-(3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (100mg, 0.25mmol, 1.00 equivalents), sodium hydroxide (20mg, 0.5mmol, 2.00 equivalents) and methyl alcohol/H ₂The solution of O (20/5mL) adds in the 50-mL round-bottomed flask.Gained solution reflux was concentrated into dried in 4 hours then.Residue uses the dilution of 15mL water and uses 3N HCl acidified aqueous solution to be pH=5.The solid that obtains is collected in filtration, and water flushing and dry generation 65mg (65%) 3-(3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid orange solids.

LC-MS：(ES，m/z)：382[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.35(s，1H)，8.14-8.06(d，J＝0.9Hz，2H)，7.74-7.70(m，2H)，7.29-7.26(t，J＝2.7Hz，3H)，6.99-6.95(t，J＝6.3Hz，1H)，6.74-6.60(m，3H)，3.80-3.75(t，J＝6.3Hz，2H)，2.75-2.70(t，J＝6.3Hz，2H)，2.02-1.93(m，2H).

Embodiment 41

3-(benzene ethylamino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(benzene ethylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents), 2-phenyl-ethyl amine hydrochloride (207.8mg; 1.32mmol, 3.00 equivalents), salt of wormwood (304.4mg, 2.21mmol; 5.00 equivalent), N, dinethylformamide (2mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Then through adding the 20mL shrend reaction of going out.Gained solution is with the 3x50mL ethyl acetate extraction and merge organic layer.With anhydrous sodium sulfate drying organic layer and vacuum concentration.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 120mg (71%) 3-(benzene ethylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：384[M+H] ⁺

Step 2.3-(benzene ethylamino)-2-phenyl quinoxaline-6-carboxylic acid

Sodium hydroxide (50.08g, 1.25mol, the 4.00 equivalents) solution that will be dissolved in 3-(benzene ethylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester (120mg, 0.31mmol, 1.00 equivalents) solution of methyl alcohol (15mL), water-soluble (2mL) adds in the 50mL round-bottomed flask.Gained solution stirred 2 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Residue dilutes with 20mL water.With hydrochloride aqueous solution (1mol/L) the pH value of this solution is adjusted to 4-5.Filter and collect the gained solid.Produce 60mg (52%) 3-(benzene ethylamino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：370[M+H] ⁺

¹H?NMR(300MHz，DMSO，ppm)：δ8.203-8.199(s，1H)，7.855(s，2H)，7.662-7.630(m，2H)，7.569-7.515(m，3H)，7.349-7.194(m，5H)，6.809-6.773(m，1H)，3.706-3.639(m，2H)，2.982-2.933(m，2H).

Embodiment 42

3-(methyl (styroyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.N-styroyl methane amide

2-phenyl-ethyl amine (1.9g, 15.70mmol, 1.00 equivalents) is added in the 100mL 3 neck round-bottomed flasks that purge and keep with the nitrogen inert atmosphere.Dropwise stir then and add ethyl formate (5g, 67.57mmol, 4.30 equivalents).50 ℃ of stirred overnight of gained solution.Vacuum concentration gained solution.With methylene chloride (70: 1) residue is put on silicagel column.Obtain 2.27g (97%) N-styroyl methane amide yellow oil.

LC-MS：(ES，m/z)：150[M+H] ⁺

Step 2.N-methyl-2-phenyl-ethyl amine

To be dissolved in the LiAlH of THF (70mL) ₄(868mg, 22.84mmol, 1.50 equivalents) solution adds in the 250mL 3 neck round-bottomed flasks that purge and keep with the nitrogen inert atmosphere.Dropwise stir N-styroyl methane amide (2.27g, 15.23mmol, the 1.00 equivalents) solution that adding is dissolved in THF (500mL) then, and the solution that obtains is kept backflow.Refluxing and stirring is spent the night in the oil bath of gained solution.Then through adding the shrend reaction of going out.The solution that obtains is used the 4x30mL dichloromethane extraction, merges organic layer and uses anhydrous sodium sulfate drying, vacuum concentration then.With methylene chloride (100: 1) residue is put on silicagel column.Obtain 1.36g (34%) N-methyl-2-phenyl-ethyl amine yellow oil.

Step 3.3-(methyl (styroyl) amino)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in N, 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, the 0.44mmol of dinethylformamide (5mL); 1.00 equivalent) solution, N-methyl-2-phenyl-ethyl amine (177.6mg; 1.32mmol, 3.00 equivalents), salt of wormwood (181.6mg; 1.32mmol, 3.00 equivalents) add in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Then through adding the shrend reaction of going out.The solution that obtains is used the 3x20mL dichloromethane extraction, merges organic layer and uses anhydrous sodium sulfate drying, vacuum concentration then.With ethyl acetate/petroleum ether (100: 1) residue is put on silicagel column.Produce 153.3mg (85%) 3-(methyl (styroyl) amino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：398[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.52-8.51(d，J＝3Hz，1H)，8.06-8.05(d，J＝3Hz，1H)，8.03-8.02(d，J＝3Hz，1H)，8.00-7.65(m，2H)，7.48-7.42(m，3H)，7.24-7.05(m，3H)，7.04-7.02(d，J＝6Hz，2H)，3.99(s，3H)，3.63-3.58(t，J＝7.5Hz，2H)，2.90-2.74(m，5H).

Step 4.3-(methyl (styroyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

3-(methyl (styroyl) amino)-2-phenyl quinoxaline-6-carboxylate methyl ester (144.7mg, 0.35mmol, 1.00 equivalents, 96%) solution that will be dissolved in methyl alcohol (20mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (72.9mg, 1.82mmol, the 5.00 equivalents) solution that adds water-soluble (2mL) then.Gained solution is stirred overnight in 50 ℃ of oil baths.Then its vacuum concentration is also diluted with 10ml water.Use the 1N hydrochloride aqueous solution that the pH regulator of the above-mentioned aqueous solution is 3-4.Filter and collect the gained solid and use methanol wash.Produce 52.6mg (38%) 3-(methyl (styroyl) amino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：384[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.28(s，1H)，7.96-7.89(m，2H)，7.65-7.62(m，2H)，7.50-7.48(t，J＝3Hz，3H)，7.22-7.03(m，5H)，3.57-3.52(t，J＝7.5Hz，2H)，2.89-2.79(m，5H).

Embodiment 43

3-(sec.-propyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(sec.-propyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in N, 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (170mg, the 0.50mmol of dinethylformamide (5mL); 1.00 equivalent) solution, N-methyl-prop-2-amine (73mg, 1.00mmol, 2.00 equivalents) and salt of wormwood (207mg; 1.50mmol, 3.00 equivalents) add in the 8-mL ST.100 ℃ of stirred overnight of the solution that obtains.Then through adding the shrend reaction of going out.Filter and collect the gained solid.Produce 109.8mg (59%) 3-(sec.-propyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：336[M+H] ⁺

Step 2.3-(sec.-propyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

3-(sec.-propyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylate methyl ester (109.8mg, 0.29mmol, 1.00 equivalents, 90%) solution that will be dissolved in methyl alcohol (20mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (65.6mg, 1.64mmol, the 5.00 equivalents) solution that adds water-soluble (3mL) then.Gained solution is stirred overnight in 50 ℃ of oil baths.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.Vacuum concentration should filtrating.Filter and collect the gained solid also with methyl alcohol and water washing.Produce 58mg (59%) 3-(sec.-propyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：322[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.26(s，1H)，7.94(s，2H)，7.86-7.83(m?2H)，7.58-7.50(m，3H)，4.25-4.16(m，1H)，2.67(s，3H)，1.05-1.02(d，J＝9Hz，6H).

Embodiment 44

3-(hexamethylene is amino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(hexamethylene is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents), hexahydroaniline (131.03mg; 1.32mmol, 3.00 equivalents), salt of wormwood (304.41mg, 2.21mmol; 5.00 equivalent) and N, dinethylformamide (2mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Then through adding the 20mL shrend reaction of going out.Obtained aqueous solution is used the 3x50mL ethyl acetate extraction.Merging organic layer also cleans with the 5x30mL sodium chloride aqueous solution.With anhydrous sodium sulfate drying organic layer and vacuum concentration.Through this residue of silica gel column chromatography purifying with ethyl acetate/petroleum ether (1: 50).Produce 80mg (46%) 3-(hexamethylene is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：362[M+H] ⁺

Step 2.3-(hexamethylene is amino)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in sodium hydroxide (44.32mg, 1.11mmol, 5.00 equivalents) the solution adding 50mL round-bottomed flask of 3-(hexamethylene is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester (80mg, 0.22mmol, 1.00 equivalents) solution of methyl alcohol (15mL), water-soluble (2mL).Gained solution stirred 2 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Residue dilutes with 20mL water.With hydrochloride aqueous solution (1mol/L) the pH value of this solution is adjusted to 4-5.Filter and collect the gained solid.Produce 60mg (76%) 3-(hexamethylene is amino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：334[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.155(s，1H)，7.879-7.850(d，J＝8.7Hz，2H)，7.815-7.772(m，2H)，7.597-7.578(m，3H)，6.248-6.222(d，J＝8.4Hz，1H)，4.091(s，1H)，1.966(m，2H)，1.694-1.598(m，3H)，1.370(m，4H)，1.239-1.181(m，1H).

Embodiment 45

3-(pipecoline-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(pipecoline-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents), pipecoline (130.86mg; 1.32mmol, 3.00 equivalents), DIEA (170.28mg, 1.32mmol; 3.00 equivalent), N, dinethylformamide (4mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Then through adding the shrend reaction of going out.Gained solution is used the 4x20mL dichloromethane extraction, merges organic layer and uses anhydrous sodium sulfate drying.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 7) residue is put on silicagel column.Produce 60mg (36%) 3-(pipecoline-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS：(ES，m/z)：362[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.580-8.575(s，1H)，(d，J＝1.5Hz，1H)，8.10-7.98(m，4H)，7.56-7.48(m，3H)，4.18-4.14(t，J＝6Hz，1H)，4.01(s，3H)，3.20-3.12(m，1H)，1.76-1.61(m，6H)，1.14-1.12(d，J＝6.9Hz，3H).

Step 2.3-(pipecoline-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

3-(pipecoline-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (107.9mg, 0.30mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (20mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (60mg, 1.50mmol, the 5.00 equivalents) solution that adds water-soluble (3mL) then.Stirred overnight in 50 ℃ of oil baths of the solution that obtains, vacuum concentration dilutes with 10ml water then.Use 1N hydrogenchloride that the pH regulator of this aqueous solution is 3-4.Filter and collect the gained solid and use methanol wash.Produce 54mg (50%) 3-(pipecoline-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：348[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.26(s，1H)，7.99-7.92(m，4H)，7.57-7.51(m，3H)，4.07-4.05(d，J＝5.7Hz，1H)，3.10-3.03(m，1H)，1.62-1.34(m，6H)，1.08-1.04(t，J＝6.6Hz，3H).

Embodiment 46

3-(cyclopropyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(cyclopropyl is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester

3-chloro-2-phenyl quinoxaline-6-carboxylate methyl ester (200mg, 0.67mmol, 1.00 equivalents), cyclopropylamine (10mL), DMSO (1mL) are added in the 20-mL ST.Gained solution is stirred overnight in 50 ℃ of oil baths.The mixture of vacuum concentration gained.The dilution of gained solution with water.Filter and collect the gained solid and it is put on silicagel column with PE/EA (50: 1).Produce 182.4mg (83%) 3-(cyclopropyl is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：320[M+H] ⁺

Step 2.3-(cyclopropyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

3-(cyclopropyl is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester (182.4mg, 0.56mmol, 1.00 equivalents, 98%) solution that will be dissolved in THF (17mL) adds in the 50mL round-bottomed flask that purges and keep with the nitrogen inert atmosphere.Add sodium hydride (274.5mg, 11.44mmol, 20.00 equivalents).Stirring at room gained solution 1 hour.Dropwise stir in 0 ℃ then and add CH ₃I (809.4mg, 5.70mmol, 10.00 equivalents).Gained solution room temperature stirring reaction spends the night.Gained mixture vacuum concentration also dilutes with 10ml water.Use 1N hydrogenchloride that the pH regulator of this aqueous solution is 3-4.Filter and collect gained solid and water and methanol wash.Produce 66.5mg (36%) 3-(cyclopropyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：320[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.26(s，1H)，7.95(s，2H)，7.80-7.78(d，J＝6Hz，2H)，7.51-7.50(d，J＝6.9Hz，3H)，3.00(s，3H)，2.45(s，1H)，0.43(s，4H).

Embodiment 47

3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents), 2-crassitude (74.8mg; 0.88mmol, 2.00 equivalents), salt of wormwood (181.6mg, 1.32mmol; 3.00 equivalent) and N, dinethylformamide (4mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Through adding the shrend reaction of going out, the solution that obtains use the 5x20mL dichloromethane extraction, and the merging organic layer is also used anhydrous sodium sulfate drying, vacuum concentration then.Through this residue of silica gel column chromatography purifying with ethyl acetate/petroleum ether (1: 100).Produce 110.3mg (72%) 3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS：(ES，m/z)：348[M+H] ⁺

Step 2.3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (110mg, 0.32mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (20mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (63.4mg, 1.58mmol, the 5.00 equivalents) solution that adds water-soluble (2.5mL) then.Gained solution stirred 8 hours in 50 ℃ of oil baths.Gained mixture vacuum concentration also dilutes with 10ml water.Use 1N hydrogenchloride that the pH regulator of this aqueous solution is 3-4.Filter and collect the gained solid and use hexane wash.Produce 40mg (38%) 3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：334[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.25(s，1H)，7.91(s，2H)，7.74-7.72(d，J＝6Hz，2H)，7.54-7.51(d，J＝9Hz，3H)，4.24-4.22(d，J＝6Hz，1H)，3.02-2.93(m，2H)，2.12(s，1H)，1.75(s，1H)，1.53(s，2H)，1.33-1.31(d，J＝6Hz，3H).

Embodiment 48

3-(sec.-butyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(sec.-butyl is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester

3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents), fourth-2-amine (193mg, 2.64mmol, 6.00 equivalents), salt of wormwood (181.6mg, 1.32mmol, 3.00 equivalents), toluene (3mL) are added in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Vacuum concentration gained solution.With ethyl acetate/petroleum ether (1: 10) residue is put on silicagel column.Produce 109mg (slightly) 3-(sec.-butyl is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS：(ES，m/z)：336[M+H] ⁺

Step 2.3-(sec.-butyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

In 3-(second month in a season-butyl amino)-2-phenyl quinoxaline-6-carboxylate methyl ester (133.6mg, 0.40mmol, 1.00 equivalents) solution that will be dissolved in THF (12mL) and sodium hydride (96mg, 4.00mmol, 10.03 equivalents) the adding 50mL round-bottomed flask.Stirring at room gained solution 1 hour.Dropwise stir then and add methyl iodide (284mg, 2.00mmol, the 5.01 equivalents) solution that is dissolved in THF (1mL).Gained solution is stirred overnight at room temperature.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.Vacuum concentration gained solution.Through this residue of silica gel column chromatography purifying with methylene dichloride/sherwood oil (10: 1).Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (130mg): post, SunFire Prep C18,5um, 19*100mm; Moving phase contains 0.05%TFA and CH ₃Water (the 60%CH of CN ₃CN brought up to 80% with 6 minutes, brought up to 100% with 1 minute, was reduced to 60% with 1 minute); Detector, UV 220254nm.Produce 52mg (39%) 3-(second month in a season-butyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：336[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.26(s，1H)，7.94(s，2H)，7.81-7.78(t，J＝9Hz，2H)，7.57-7.51(m，3H)，3.99-3.92(q，J＝9Hz，1H)，2.67(s，3H)，1.56-1.37(m，2H)，1.02-1.00(d，J＝4Hz，3H)，0.65-0.60(t，J＝6Hz，3H).

Embodiment 49

(R)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1. (R)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents); (R)-tetramethyleneimine-3-alcohol hydrochloride (212mg, 1.72mmol, 4.00 equivalents), salt of wormwood (200mg; 1.55mmol, 3.00 equivalents), toluene (5mL), DMSO (1.7mL) adds in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Then through adding the 20ml shrend reaction of going out.The solution that obtains is used the 5x10mL dichloromethane extraction, merges organic layer and vacuum concentration.With methylene chloride (70: 1) residue is put on silicagel column.Produce 147.4mg (95%) (R)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS(ES，m/z)：350[M+H] ⁺

Step 2. (R)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

(R)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (147.4mg, 0.42mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (84.5mg, 2.11mmol, the 5.00 equivalents) solution that adds water-soluble (2mL) then.Gained solution is stirred overnight in 50 ℃ of oil baths.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (120mg): post, SunFirePrep C18,5um, 19*100mm; Moving phase contains 0.05%TFA and CH ₃Water (the 20%CH of CN ₃CN brought up to 50% with 6 minutes, brought up to 100% with 1 minute, was reduced to 20% with 1 minute); Detector, UV 220 254nm.Produce 35mg (24%) (R)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：336[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.34(s，1H)，8.24-7.49(m，7H)，4.21(s，1H)，3.53-3.27(m，3H)，3.00-2.96(d，J＝16Hz，1H)，1.89-1.52(m，2H).

Embodiment 50

(S)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1. (S)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents); (S)-tetramethyleneimine-3-alcohol hydrochloride (163mg, 1.32mmol, 4.00 equivalents), DIEA (227mg; 1.76mmol, 4.00 equivalents), toluene (4mL), DMSO (2mL) adds in the 8-mL ST.Gained solution stirred 7 hours in 100 ℃.Then through adding the shrend reaction of going out.The solution that obtains is used the 5x15mL dichloromethane extraction, merges organic layer and vacuum concentration.Through this residue of silica gel column chromatography purifying with methylene chloride (70: 1).Produce 176mg (rough) (S)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：350[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.56(s，1H)，8.04-7.96(m，2H)，7.75-7.73(t，J＝1.5Hz，2H)，7.54-7.46(m，3H)，4.50(s，1H)，4.00(s，3H)，3.70-3.30(m，4H)，2.00(s，2H).

Step 2. (S)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

(S)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (170mg, 0.49mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (20mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (97.4mg, 2.44mmol, the 5.00 equivalents) solution that adds water-soluble (2.5mL) then.Gained solution is stirred overnight in 50 ℃ of oil baths.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.Filter and collect gained solid and water and methanol wash.This solid is dry in baking oven.Produce 40mg (25%) (S)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：336[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.32-8.24(d，J＝24Hz，1H)，7.94-7.86(m，2H)，7.70-7.68(m，J＝2.1Hz，2H)，7.54-7.52(d，J＝6Hz，3H)，4.89(s，1H)，4.22(s，1H)，3.55-3.49(m，2H)，3.00-2.96(d，J＝12Hz，1H)，1.89-1.79(m，2H).

Embodiment 51

(R)-3-(2-(methoxymethyl) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1. (S)-3-(2-(methoxymethyl) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With (S)-2-(methoxymethyl) tetramethyleneimine (96.45mg; 0.85mmol; 5.00 equivalent), 3-chloro-2-phenyl quinoxaline-6-carboxylate methyl ester (50mg, 0.17mmol, 1.00 equivalents), salt of wormwood (46.7mg; 0.34mmol, 2.00 equivalents), toluene/DMSO (2/0.4mL) adds in the 10-mL pressure-pot reactor drum.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.Then through adding the 10mL shrend reaction of going out.Gained solution is with the 3x30mL ethyl acetate extraction and merge organic layer.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 17mg (27%) (S)-3-(2-(methoxymethyl) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS(ES，m/z)：378[M+H] ⁺

Step 2. (R)-3-(2-(methoxymethyl) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

(R)-3-(2-(methoxymethyl) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (66mg, 0.18mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Sodium hydroxide (35mg, 0.88mmol, the 5.00 equivalents) solution that adds water-soluble (2mL) then.Gained solution stirred 2 hours in 50 ℃ of oil baths.Gained mixture vacuum concentration also dilutes with 20ml water.(1mol/L) is adjusted to 4-5 with this pH value of aqueous solution with hydrogenchloride.Filter and collect the gained solid.With methylene chloride (10: 1) residue is put on silicagel column.Produce 25mg (39%) (R)-3-(2-(methoxymethyl) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：364[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.12(s，1H)，8.243-8.239(d，J＝1.2Hz，1H)，7.95-7.88(m，2H)，7.75-7.72(m，2H)，7.56-7.49(m，3H)，4.51-4.47(m，1H)，3.70-3.65(m，1H)，3.52-3.47(m，1H)，3.32-3.30(d，J＝5.1Hz?1H)，2.96-2.93(m，2H)，2.06-2.03(m，1H)，1.82-1.74(m，2H)，1.58-1.55(m，1H).

Embodiment 52

(R)-3-(2-(methylol) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Base) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in 3-chloro-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg of Tol/DMSO (2.5/0.5mL); 0.50mmol; 1.00 (R)-tetramethyleneimine-2-base methyl alcohol (150mg, 1.49mmol, 3.00 equivalents) and salt of wormwood (345mg equivalent); 2.50mmol, 5.00 equivalents) solution add in the 8-mL ST.100 ℃ of stirred overnight of the mixture that obtains.Through this residue of silica gel column chromatography purifying with ethyl acetate/petroleum ether (1: 50).Produce 120mg (63%) (R)-3-(2-(methylol) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：364[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.26(d，J＝1.5Hz，1H)，7.97-7.87(m，2H)，7.80-7.77(dd，J＝1.8，7.6Hz，2H)，7.56-7.46(m，3H)，4.78-4.74(t，J＝5.7Hz，1H)，4.36-4.32(t，J＝4.5Hz，1H)，3.93(s，3H)，3.72-3.67(q，J＝5.4Hz，2H)，2.97-2.92(m，2H)，2.04-1.75(m，4H).

Step 2. (R)-3-(2-(methylol) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in (R)-3-(2-(methylol) tetramethyleneimine-1-the yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (120mg of methanol (20/5mL); 0.33mmol; 1.00 equivalent) and the solution of sodium hydroxide (66mg, 1.65mmol, 4.99 equivalents) add in the 100-mL round-bottomed flask.70 ℃ of stirring reactions 5 hours also are concentrated into dried.Residue is dissolved in the 20mL water and cleans with 10mL EtOAc.With 1N HCl with the pH of water layer be adjusted to 7 and with DCM/MeOH (10/1,20mLx5) extract.Merge organic layer and use Na ₂SO ₄Drying, and be concentrated into dried.Produce 80mg (66%) (R)-3-(2-(methylol) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：350[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.21(s，1H)，7.94-7.90(d，J＝8.1Hz，1H)，7.82-7.76(m，3H)，7.53-7.45(m，3H)，4.35(s，1H)，3.69-3.67(d，J＝3.9Hz，2H)，3.00-2.89(m，2H)，2.02-1.97(m，1H)，1.91-1.74(m，2H)，1.58-1.49(m，1H).

Embodiment 53

(S)-3-(2-(methylol) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1. (S)-3-(2-(methylol) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

To be dissolved in 3-chloro-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg of Tol/DMSO (2.5/0.5mL); 0.50mmol; 1.00 (S)-tetramethyleneimine-2-base methyl alcohol (150mg, 1.49mmol, 3.00 equivalents) and salt of wormwood (345mg equivalent); 2.50mmol, 5.00 equivalents) solution add in the 8-mL ST.100 ℃ of stirred overnight of the mixture that obtains.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 104mg (54%) (S)-3-(2-(methylol) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：364[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：

8.26(d，J＝1.5Hz，1H)，7.97-7.87(m，2H)，7.80-7.77(m，2H)，7.55-7.47(m，3H)，4.78-4.73(t，J＝5.7Hz，1H)，4.35-4.32(d，J＝4.5Hz，1H)，3.93(s，3H)，3.76-3.67(m，2H)，3.00-2.92(m，2H)，1.99-1.49(m，4H).

Step 2. (S)-3-(2-(methylol) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in (S)-3-(2-(methylol) tetramethyleneimine-1-the yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (104mg of methanol (20/5mL); 0.29mmol; 1.00 equivalent) and the solution of sodium hydroxide (57.3mg, 1.43mmol, 5.00 equivalents) add in the 100-mL round-bottomed flask.React on 70 ℃ and stirred 5 hours, be concentrated into driedly, be dissolved in the 20mL water and clean with 10mL EtOAc.With 1N HCl with the pH of water layer be adjusted to 7 and with DCM/MeOH (10/1,20mLx5) extract.Merge organic layer, use Na ₂SO ₄Drying, and vacuum concentration.Produce 45mg (43%) (S)-3-(2-(methylol) tetramethyleneimine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：350[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.23(d，J＝0.6Hz，1H)，7.93-7.86(m，2H)，7.80-7.77(m，2H)，7.55-7.48(m，3H)，4.75(s，1H)，4.34(t，J＝3Hz，1H)，3.73-3.64(m，2H)，2.97-2.91(m，2H)，2.01-1.96(m，1H)，1.89-1.75(m，2H)，1.58-1.53(m，1H).

Embodiment 54

3-(3-methylmorpholine generation)-2-phenyl quinoxaline-6-carboxylic acid

Step 1. (E)-2-(4-methoxyl group tolylene is amino) third-1-alcohol

With 4-methoxybenzaldehyde (54.4g; 400.00mmol; 1.00 equivalent), the amino third-1-alcohol of 2-(30g, 400.00mmol, 1.00 equivalents), 4-toluene sulfonic acide (3.84g; 20.21mmol, 0.05 equivalent), toluene (300mL) adds with in nitrogen inert atmosphere purging and the 500mL 3 neck round-bottomed flasks kept.Gained solution reflux in oil bath spends the night.The mixture of vacuum concentration gained.The gained mixture cleans with the 3x50mL hexane.Filter and collect the gained solid.Produce 63g (82%) E)-2-(4-methoxyl group tolylene is amino) third-1-alcohol white solid.

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.289(s，1H)，7.713-7.666(m，2H)，6.960-6.913(m，2H)，3.861(s，3H)，3.712-3.693(d，J＝5.7Hz，2H)，3.522-3.460(m，1H)，1.255-1.240(t，J＝4.5Hz，3H).

Step 2.2-(the 4-methoxy-benzyl is amino) third-1-alcohol

(E)-2-(4-methoxyl group tolylene is amino) third-1-alcohol (15g, 77.72mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (150mL) adds in the 250mL 3 neck round-bottomed flasks.Criticize in-10-0 ℃ a mark then and add NaBH ₄(5.88g, 155.56mmol, 2.00 equivalents).Gained solution stirred 2 hours in-10-0 ℃ ice/salt bath.Gained mixture vacuum concentration also dilutes with 200ml water.The aqueous solution that obtains is used the 3x100mL ethyl acetate extraction, merges organic layer and uses anhydrous magnesium sulfate drying, vacuum concentration then.Produce 11.1g (73%) 2-(the 4-methoxy-benzyl is amino) third-1-alcohol white solid.

LC-MS：(ES，m/z)：196[M+H] ⁺

¹H?NMR(300MHz，CDCl ₃，ppm)：δ7.281-7.251(d，J＝6Hz，2H)，6.907-6.860(m，2H)，3.817(s，3H)，3.722-3.592(m，2H)，3.323-3.264(m，1H)，2.887-2.830(m，1H)，1.120-1.098(d，J＝6.6Hz，3H)

Step 3.N-(4-methoxy-benzyl)-2-bromo-N-(1-hydroxyl third-2-yl) ethanamide

2-(the 4-methoxy-benzyl is amino) third-1-alcohol (11g, 56.41mmol, 1.00 equivalents) solution that will be dissolved in methylene dichloride (100mL) adds in the 250mL 3 neck round-bottomed flasks that purge and keep with the nitrogen inert atmosphere.Add triethylamine (5.7g, 56.44mmol, 1.00 equivalents) then.Dropwise stir 2-acetyl bromide bromide (11.4g, 56.44mmol, the 1.00 equivalents) solution that adding is dissolved in methylene dichloride (50mL) in-17～-25 ℃.Gained solution stirred 1 hour in-17～-25 ℃ of liquid nitrogen baths.The gained mixture cleans with 3x100mL water.With anhydrous magnesium sulfate drying organic layer and vacuum concentration.Produce 16g (90%) N-(4-methoxy-benzyl)-2-bromo-N-(1-hydroxyl third-2-yl) ethanamide yellow oil.

LC-MS：(ES，m/z)：316[M+H] ⁺

Step 4.4-(4-methoxy-benzyl)-5-methylmorpholine-3-ketone

Sodium hydride (3.46g, 100.92mmol, 2.00 equivalents, the 70%) solution that will be dissolved in THF (200mL) adds in the 500mL 3 neck round-bottomed flasks that purge and keep with the nitrogen inert atmosphere.Dropwise stir in 25 ℃ then and add N-(4-methoxy-benzyl)-2-bromo-N-(1-hydroxyl third-2-yl) ethanamide (16g, 50.47mmol, the 1.00 equivalents) solution that is dissolved in THF (100mL).Gained solution is stirred overnight in 25 ℃ of oil baths.Then through adding 200g water/ice cancellation reaction.Gained solution is with the 5x200mL dichloromethane extraction and merge organic layer.Clean organic layer with 3x50mL water.With anhydrous magnesium sulfate drying and vacuum concentration.Produce 11.9g (rough) 4-(4-methoxy-benzyl)-5-methylmorpholine-3-ketone yellow oil.

LC-MS：(ES，m/z)：236[M+H] ⁺

Step 5.4-(4-methoxy-benzyl)-3-methylmorpholine

To be dissolved in the LiAlH of THF (100mL) ₄(3.83g, 100.79mmol, 2.00 equivalents) solution adds in the 250mL 3 neck round-bottomed flasks that purge and keep with the nitrogen inert atmosphere.Dropwise stir in 0 ℃ then and add 4-(4-methoxy-benzyl)-5-methylmorpholine-3-ketone (11.9g, 50.42mmol, the 1.00 equivalents) solution that is dissolved in THF (50mL).Gained solution reflux 1 hour and reduce to room temperature in oil bath.Gained solution dilutes with 100mL water.Gained solution is used the 3x200mL ethyl acetate extraction, merges organic layer and uses anhydrous magnesium sulfate drying, vacuum concentration then.With ethyl acetate/petroleum ether (1: 30) residue is put on silicagel column.Produce 7g (58%) 4-(4-methoxy-benzyl)-3-methylmorpholine yellow oil.

LC-MS：(ES，m/z)：222[M+H] ⁺

Step 6.3-methylmorpholine

4-(4-methoxy-benzyl)-3-methylmorpholine (7g, 31.53mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (70mL) adds in the 250mL round-bottomed flask that purges and keep with the nitrogen inert atmosphere.Add then palladium carbon (10%, 2g).Import H then ₂(g).Stirred overnight in 50 ℃ of oil baths of the solution that obtains.Leach solid.Vacuum concentration gained solution.Produce 2.1g (66%) 3-methylmorpholine yellow oil.

LC-MS：(ES，m/z)：102[M+H] ⁺

Step 7.3-(3-methylmorpholine generation)-2-phenyl quinoxaline-6-carboxylate methyl ester

The 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents) and the 3-methylmorpholine (443mg, 4.39mmol, 10.00 equivalents) that will be dissolved in DMSO (1mL) add in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The reaction mixture vacuum concentration.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 46mg (29%) 3-(3-methylmorpholine generation)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：364[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.615-8.609(d，J＝1.8Hz，1H)，8.158-7.984(m，4H)，7.574-7.502(m，3H)，4.053-3.403(m，10H)，1.218-1.196(d，J＝6.6Hz，3H).

Step 8.3-(3-methylmorpholine generation)-2-phenyl quinoxaline-6-carboxylic acid

3-(3-methylmorpholine generation)-2-phenyl quinoxaline-6-carboxylate methyl ester (45mg, 0.12mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (10mL) adds in the 50mL round-bottomed flask.Sodium hydroxide (25mg, 0.62mmol, the 5.00 equivalents) solution that adds water-soluble (2mL) then.Gained solution stirred 2 hours in 50 ℃ of oil baths.Gained mixture vacuum concentration.Residue dilutes with 20mL water.(1mol/L) is adjusted to 4-5 with above-mentioned pH value of aqueous solution with hydrochloride aqueous solution.Filter and collect the gained solid.Produce 40mg (90%) 3-(3-methylmorpholine generation)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：350[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.257(s，1H)，8.310(s，1H)，8.037-7.963(m，4H)，7.585-7.504(m，3H)，3.818-3.770(m，2H)，3.732-3.437(m，3H)，3.312-3.171(m，2H)，1.074-1.096(d，J＝6.6Hz，3H).

Embodiment 55

(S)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1. (S)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (500mg, 1.67mmol, 1.00 equivalents), 2-crassitude (285mg; 2.92mmol, 2.00 equivalents), salt of wormwood (693.8mg, 4.01mmol; 3.00 equivalent) and N, dinethylformamide (6mL) adds in the 20-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Then through adding the shrend reaction of going out.The solution that obtains is used the 12x20mL dichloromethane extraction, merges organic layer and uses anhydrous sodium sulfate drying, vacuum concentration then.With ethyl acetate/petroleum ether (1: 100) residue is put on silicagel column.Produce 590.7mg (92%) 3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow oil.Then isomer is carried out the chirality preparation HPLC to obtain product (S)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (193.6mg).

LC-MS：(ES，m/z)：348[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.26-8.25(d，J＝1.5Hz，1H)，7.96-7.87(m，2H)，7.75-7.71(m，2H)，7.57-7.47(m，3H)，4.27-4.20(m，1H)，3.93(s，3H)，3.01-2.93(m，2H)，2.11(s，1H)，1.76-1.75(d，J＝3Hz，1H)，1.56-1.50(m，2H)，1.34-1.32(d，J＝6Hz，3H).

Step 2. (S)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

(S)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (193.6mg, 0.56mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Sodium hydroxide (111.6mg, 2.79mmol, the 5.00 equivalents) solution that adds water-soluble (1.5mL) then.Stirred overnight and be concentrated into dried in 50 ℃ of oil baths of the solution that obtains.Residue is adjusted to 3-4 with the dilution of 10mL water and with 1N hydrogenchloride with pH.Filter and collect the gained solid.Produce 130mg (69%) (S)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS(ES，m/z)：334[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：

8.25(s，1H)，7.94-7.87(m，2H)，7.75-7.73(d，J＝6Hz，2H)，7.56-7.49(m，3H)，4.27-4.21(m，1H)，3.02-2.94(m，2H)，2.12(s，1H)，1.75(s，1H)，1.56-1.51(m，2H)，1.34-1.32(d，J＝6Hz，3H).

Embodiment 56

(S)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1. (R)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (500mg, 1.67mmol, 1.00 equivalents), 2-crassitude (285mg; 2.92mmol, 2.00 equivalents), salt of wormwood (693.8mg, 4.01mmol; 3.00 equivalent) and N, dinethylformamide (6mL) adds in the 20-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Then through adding the shrend reaction of going out.The aqueous solution that obtains is used the 12x20mL dichloromethane extraction, merges organic layer and uses anhydrous sodium sulfate drying, vacuum concentration then.With ethyl acetate/petroleum ether (1: 100) residue is put on silicagel column.Produce 590.7mg (92%) 3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow oil.Then isomer is carried out the chirality preparation HPLC to obtain product (R)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (178mg).

LC-MS：(ES，m/z)：348[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.26-8.25(d，J＝3Hz，1H)，7.96-7.88(m，2H)，7.74-7.71(m，2H)，7.55-7.47(m，3H)，4.22(s，1H)，3.92(s，3H)，2.98(m，2H)，2.11(s，1H)，1.75(s，1H)，1.53(m，2H)，1.33-1.31(d，J＝6Hz，3H).

Step 2. (R)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

(R)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (178mg, 0.51mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Sodium hydroxide (102.6mg, 2.56mmol, the 5.00 equivalents) solution that adds water-soluble (1.5mL) then.Stirred overnight and be concentrated into dried in 50 ℃ of oil baths of the solution that obtains.Residue uses the dilution of 10ml water and uses 1N hydrogenchloride that the pH regulator of this aqueous solution is 3-4.Filter and collect the gained solid as product.Produce 130mg (75%) (R)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：334[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.25(s，1H)，7.94-7.87(m，2H)，7.75-7.73(d，J＝6Hz，2H)，7.56-7.49(m，3H)，4.25-4.23(d，J＝6Hz，1H)，3.02-2.94(m，2H)，2.12(s，1H)，1.75(s，1H)，1.54(s，2H)，1.34-1.32(d，J＝6Hz，3H).

Embodiment 57

2-(4-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

Step 1.2-(4-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (40mg, 0.14mmol, 1.00 equivalents), 4-fluorophenyl boric acid (57.4mg, 0.41mmol, 3.00 equivalents), Pd (PPh ₃) ₄(31.4mg, 0.03mmol, 0.20 equivalent), K ₃PO ₄(116mg, 0.55mmol, 4.00 equivalents), 1,4-two

Alkane (3mL) adds in the 10-mL ST.Stirred overnight in 110 ℃ of oil baths of the solution that obtains.Leach solid.Vacuum concentration should filtrating.Through this residue of preparation type TLC purifying with ethyl acetate/petroleum ether (1: 8).Produce 42mg (87%) 2-(4-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：354[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.600-8.595(d，J＝1.5Hz，1H)，8.094-7.903(m，4H)，7.281-7.180(m，2H)，4.295-4.251(m，1H)，4.006(s，3H)，2.779(s，3H)，1.127-1.105(d，J＝6.6Hz，6H).

Step 2.2-(4-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

2-(4-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (40mg, 0.11mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (10mL) adds in the 50mL round-bottomed flask.Sodium hydroxide (22.67mg, 0.57mmol, the 5.00 equivalents) solution that adds water-soluble (1mL) then.Gained solution stirred 5 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Then through adding the 20mL shrend reaction of going out.(1mol/L) is adjusted to 4-5 with above-mentioned pH value of aqueous solution with hydrochloride aqueous solution.Filter and collect the gained solid.Produce 30mg (76%) 2-(4-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：340[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.192(s，1H)，8.264(s，1H)，7.946-7.897(m，4H)，7.404-7.346(m，2H)，4.189-4.146(m，1H)，2.671(s，3H)，1.053-1.032(d，J＝6.3Hz，6H).

Embodiment 58

3-(sec.-propyl (methyl) amino)-2-(4-p-methoxy-phenyl) quinoxaline-6-carboxylic acid

Step 1.3-(sec.-propyl (methyl) amino)-2-(4-p-methoxy-phenyl) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (40mg, 0.14mmol, 1.00 equivalents), 4-anisole ylboronic acid (62.6mg, 0.41mmol, 3.00 equivalents), Pd (PPh ₃) ₄(31.4mg, 0.03mmol, 0.20 equivalent), K ₃PO ₄(116mg, 0.55mmol, 4.00 equivalents), 1,4-two

Alkane (3mL) adds in the 10-mL ST.Stirred overnight in 110 ℃ of oil baths of the solution that obtains.Leach solid.Vacuum concentration should filtrating.Through this residue of preparation type TLC purifying with ethyl acetate/petroleum ether (1: 8).Produce 40mg (80%) 3-(sec.-propyl (methyl) amino)-2-(4-p-methoxy-phenyl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：366[M+H] ⁺

Step 2.3-(sec.-propyl (methyl) amino)-2-(4-p-methoxy-phenyl) quinoxaline-6-carboxylic acid

3-(sec.-propyl (methyl) amino)-2-(4-p-methoxy-phenyl) quinoxaline-6-carboxylate methyl ester (40mg, 0.11mmol, the 1.00 equivalents) solution that will be dissolved in methyl alcohol (10mL) adds in the 50mL round-bottomed flask.Sodium hydroxide (21.9mg, 0.55mmol, the 5.00 equivalents) solution that adds water-soluble (1mL) then.Gained solution stirred 5 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Then through adding the 20mL shrend reaction of going out.Use the 1N hydrochloride aqueous solution that the pH regulator of the above-mentioned aqueous solution is 4-5.Filter and collect the gained solid.Produce 25mg (65%) 3-(sec.-propyl (methyl) amino)-2-(4-p-methoxy-phenyl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：352[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.141(s，1H)，8.243(s，1H)，7.955-7.840(m，4H)，7.105-7.076(d，J＝8.7Hz，2H)，4.237-4.194(m，1H)，3.842(s，3H)，2.683(s，3H)，1.059-1.037(d，J＝6.6Hz，6H).

Embodiment 59

(R)-3-(methyl (1-phenylethyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1. (R)-2-phenyl-3-(1-benzene ethylamino) quinoxaline-6-carboxylate methyl ester

3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents), (R)-1-phenyl-ethyl amine (4mL) are added in the 8mL pressure-pot reactor drum.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.With ethyl acetate/petroleum ether (1: 5) residue is put on silicagel column.Produce 144mg (81%) (R)-2-phenyl-3-(1-benzene ethylamino) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：384[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.56(s，1H)，8.51(s，1H)，8.50-4.25(m，12H)，5.60-5.59(d，J＝3Hz，2H)，4.00(s，3H)，1.62-1.60(t，J＝3Hz，3H).

Step 2. (R)-3-(methyl (1-phenylethyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in (R)-2-phenyl-3-(1-benzene ethylamino) quinoxaline-6-carboxylate methyl ester (141mg of THF (20mL); 0.37mmol, 1.00 equivalents) and solution, sodium hydride (294.5mg, 7.36mmol; 20.00 equivalent, 60%) add in the 50mL round-bottomed flask that purges and keep with the nitrogen inert atmosphere.Gained solution stirred 1 hour in room temperature ice/salt bath.Dropwise stir in 0 ℃ then and add the CH that is dissolved in THF (1mL) ₃I (522.8mg, 3.68mmol, 10.00 equivalents) solution.20 ℃ of stirred overnight of the solution that obtains.Use the 1N hydrochloride aqueous solution that the pH regulator of above-mentioned solution is 3-4.The mixture of vacuum concentration gained.With methylene chloride (10: 1) residue is put on silicagel column.Produce 57mg (39%) (R)-3-(methyl (1-phenylethyl) amino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：384[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.24(s，1H)，8.01-7.99(d，J＝3Hz，1H)，7.91-7.83(m，3H)，7.54-7.47(m，3H)，7.36-7.22(m，5H)，5.45-5.42(d，J＝9Hz，1H)，2.50-2.46(d，J＝12Hz，3H)，1.48-1.46(d，J＝6Hz，3H).

Embodiment 60

(S)-3-(methyl (1-phenylethyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1 (S)-2-phenyl-3-(1-phenyl ethylamino) quinoxaline-6-carboxylate methyl ester

3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents), (S)-1-phenyl-ethyl amine (4mL) are added in the 8mL pressure-pot reactor drum.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 78mg (46%) (S)-2-phenyl-3-(1-phenyl ethylamino) quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS：(ES，m/z)：384[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.43-8.42(d，J＝3Hz，1H)，8.02-7.92(m，2H)，7.78-7.75(m，2H)，7.63-7.56(m，3H)，7.43-7.25(m，6H)，5.52-5.51(t，J＝3Hz，2H)，4.00(s，3H)，1.62-1.56(m，4H).

Step 2. (S)-3-(methyl (1-phenylethyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in (S)-2-phenyl-3-(1-phenyl ethylamino) quinoxaline-6-carboxylate methyl ester (110mg of THF (9mL); 0.29mmol, 1.00 equivalents) and solution, sodium hydride (137.9mg, 5.74mmol; 20.00 equivalent, 60%) add in the 50mL round-bottomed flask that purges and keep with the nitrogen inert atmosphere.Gained solution stirred 1 hour in room temperature ice/salt bath.Dropwise stir in 0 ℃ then and add the CH that is dissolved in THF (1mL) ₃I (407.8mg, 2.87mmol, 10.00 equivalents) solution.Stirred overnight in 20 ℃ of ice/salt baths of the solution that obtains.Use 1N hydrogenchloride that the pH regulator of this solution is 3-4.The mixture of vacuum concentration gained.With methylene chloride (10: 1) residue is put on silicagel column.Produce 40mg (36%) (S)-3-(methyl (1-phenylethyl) amino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：384[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.26(s，1H)，8.02-7.95(m，2H)，7.89-7.85(m，2H)，7.57-7.50(m，3H)，7.34-7.25(m，5H)，5.55-5.48(m，1H)，2.51-2.48(d，J＝6Hz，3H)，1.51-1.49(d，J＝6Hz，3H).

Embodiment 61

(R)-3-(sec.-butyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1. (R)-3-(sec.-butyl is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester

3-bromo-2-phenyl quinoxaline-6-carboxylic acid (150mg, 0.439mmol, 1.00 equivalents), (S)-Ding-2-amine (2mL), DMSO (1mL) are added in the 8-mL ST.Gained solution is stirred overnight in 60 ℃ of oil baths.Gained mixture vacuum concentration and dilute with water.Filter and collect the gained solid.With PE/EA (50: 1) residue is put on silicagel column.Produce 114mg (R)-3-(sec.-butyl is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS：(ES，m/z)：336[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.49(s，1H)，8.01-7.95(m，2H)，7.75-7.72(m，2H)，7.63-7.54(m，3H)，5.09-5.07(d，J＝6Hz，1H)，4.40-4.31(m，1H)，4.00(s，3H)，1.66-1.57(m，2H)，1.26-1.24(d，J＝6Hz，3H)，1.00-0.95(t，J＝7.2Hz，3H).

Step 2. (R)-3-(sec.-butyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in (R)-3-(sec.-butyl the is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester (110mg of THF (9mL); 0.33mmol, 1.00 equivalents) and solution, sodium hydride (132mg, 3.3mmol; 10.00 equivalent, 60%) add in the 50mL round-bottomed flask that purges and keep with the nitrogen inert atmosphere.Stirring at room gained solution 1 hour.Dropwise stir in 0 ℃ then and add the CH that is dissolved in THF (2mL) ₃I (922.5mg, 6.50mmol, 20.00 equivalents) solution.20 ℃ of stirred overnight of the solution that obtains.Gained mixture vacuum concentration also dilutes with 10ml water.Use 1N hydrogenchloride that the pH regulator of this aqueous solution is 3-4.Filter and collect the gained solid.Produce 67mg (59%) (R)-3-(sec.-butyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：336[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.26(s，1H)，7.94(s，2H)，7.82-7.80(t，J＝1.8Hz，2H)，7.59-7.49(m，3H)，3.99-3.92(m，1H)，2.68(s，3H)，2.59-1.35(m，2H)，1.03-1.01(d，J＝6Hz，3H)，0.66-0.61(t，J＝6Hz，3H).

Embodiment 62

3-(1H-indoles-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(1H-indoles-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

3-(indoline-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.39mmol, 1.00 equivalents), DDQ (447mg, 1.97mmol, 4.00 equivalents), DMSO (3mL) are added in the 10-mL ST.Stirred overnight in 30 ℃ of oil baths of the solution that obtains.Gained solution dilutes with 20mL water.Filter and collect the gained solid and it is put on silicagel column with ethyl acetate/petroleum ether (1: 50).Produce 30mg (20%) 3-(1H-indoles-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：380[M+H] ⁺

Step 2.3-(1H-indoles-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

3-(1H-indoles-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (40mg, 0.11mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (10mL) adds in the 50mL round-bottomed flask.Sodium hydroxide (21.1mg, 0.53mmol, the 5.00 equivalents) solution that adds water-soluble (2mL) then.Gained solution stirred 2 hours in 50 ℃ of oil baths.The reaction mixture vacuum concentration.Gained solution dilutes with 20mL water.Use the 1N hydrochloride aqueous solution that the pH regulator of the above-mentioned aqueous solution is 4-5.Filter and collect the gained solid.Be further purified crude product (50mg) through quick preparation HPLC with following condition (IntelFlash-1): post, silica gel; Moving phase, H ₂O/CH ₃CN=100: bring up to H in 1,40 minute ₂O/CH ₃CN=100: 60; Detector, UV 254nm.Produce 15mg (38%) 3-(1H-indoles-1-yl)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：366[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.442-8.351(m，2H)，8.088-8.059(m，1H)，7.658-7.599(m，2H)，7.429-7.272(m，8H)，7.176-7.102(m，2H)，6.601-6.591(d，J＝3Hz，1H).

Embodiment 63

2-(3, the 4-difluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

Step 1.2-(3, the 4-difluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (150mg, 0.51mmol, 1.00 equivalents), 3,4-difluorophenyl boric acid (241mg, 1.54mmol, 3.00 equivalents), Pd (PPh ₃) ₄(118mg, 0.10mmol, 0.20 equivalent), K ₃PO ₄(433mg, 2.05mmol, 4.00 equivalents), 1,4-two

Alkane (5mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 30) residue is put on silicagel column.Produce 100mg (53%) 2-(3, the 4-difluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：372[M+H] ⁺

Step 2.2-(3, the 4-difluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

2-(3, the 4-difluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (90mg, 0.24mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Sodium hydroxide (49mg, 1.23mmol, the 5.05 equivalents) solution that adds water-soluble (2mL) then.Gained solution stirred 2 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Gained solution dilutes with 20mL water.(1mol/L) is adjusted to 4-5 with this pH value of aqueous solution with hydrochloride aqueous solution.Filter and collect the gained solid.Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (90mg): post, SunFire Prep C18,5um, 19*150mm; Moving phase contains 0.05%TFA and CH ₃Water (the 60%CH of CN ₃CN brought up to 90% with 8 minutes, brought up to 100% with 1.5 minutes); Detector, UV 220254nm.Produce 25mg (28%) 2-(3, the 4-difluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：358[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.194(s，1H)，8.266(s，1H)，7.960-7.918(m，3H)，7.717-7.704(d，J＝3.9Hz，1H)，7.630-7.595(m，1H)，4.173-4.129(m，1H)，2.677(s，3H)，1.064-1.042(d，J＝6.6Hz，6H).

Embodiment 64

2-(4-chloro-phenyl-)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

Step 1.2-(4-chloro-phenyl-)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (200mg, 0.68mmol, 1.00 equivalents), 4-chlorophenylboronic acid (162mg, 1.03mmol, 3.00 equivalents), Pd (PPh ₃) ₄(157mg, 0.14mmol, 0.20 equivalent), K ₃PO ₄(578mg, 2.74mmol, 4.00 equivalents), 1,4-two

Alkane (5mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 30) residue is put on silicagel column.Produce 50mg (20%) 2-(4-chloro-phenyl-)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：370[M+H] ⁺

Step 2.2-(4-chloro-phenyl-)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

To be dissolved in 2-(4-chloro-phenyl-)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (98mg of methyl alcohol (15mL); 0.27mmol; 1.00 equivalent) sodium hydroxide of solution, water-soluble (2mL) (53mg, 1.32mmol, 5.00 equivalents) solution adds in the 50mL round-bottomed flask.Gained solution stirred 2 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Gained solution dilutes with 20mL water.(1mol/L) is adjusted to 4-5 with above-mentioned pH value of aqueous solution with hydrochloride aqueous solution.Filter and collect the gained solid.Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (80mg): post, SunFire Prep C18,5um, 19*150mm; Moving phase contains 0.05%TFA and CH ₃Water (the 60%CH of CN ₃CN brought up to 90% with 8 minutes, brought up to 100% with 1.5 minutes); Detector, UV 220254nm.Produce 25mg (25%) 2-(4-chloro-phenyl-)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：356[M+H] ⁺

¹H?NMR(300MHz，DMSO，ppm)：δ8.265(s，1H)，7.953-7.950(d，J＝0.9Hz，2H)，7.907-7.878(m，2H)，7.626-7.597(m，2H)，4.220-4.134(m，1H)，2.671(s，3H)，1.062-1.040(d，J＝6.6Hz，6H).

Embodiment 65

(R)-2-phenyl-3-(2-(trifluoromethyl) tetramethyleneimine-1-yl) quinoxaline-6-carboxylic acid

Step 1. (R)-2-phenyl-3-(2-(trifluoromethyl) tetramethyleneimine-1-yl) quinoxaline-6-carboxylate methyl ester

3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (100mg, 0.29mmol, 1.00 equivalents), (R)-2-(trifluoromethyl) tetramethyleneimine (95mg, 0.68mmol, 2.36 equivalents), n-BuOH (1.5mL) are added in the 8-mL ST.Gained solution stirred 3 days in 110 ℃.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 10) residue is put on silicagel column.Produce 30mg (26%) (R)-2-phenyl-3-(2-(trifluoromethyl) tetramethyleneimine-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：402[M+H] ⁺

Step 2. (R)-2-phenyl-3-(2-(trifluoromethyl) tetramethyleneimine-1-yl) quinoxaline-6-carboxylic acid

With (R)-2-phenyl-3-(2-(trifluoromethyl) tetramethyleneimine-1-yl) quinoxaline-6-carboxylate methyl ester (40mg, 0.10mmol, 1.00 equivalents), sodium hydroxide (20mg, 0.50mmol, 5.00 equivalents), methyl alcohol (5mL), water (1mL) adds in the 25mL round-bottomed flask.Gained solution stirred 5 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Residue dilutes with 5mL water.Using the 1N aqueous hydrochloric acid is 4 with the pH regulator of the above-mentioned aqueous solution.Filter and collect the gained solid.Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (50mg): post, SunFire Prep C18,5um, 19*150mm; Moving phase contains 0.05%TFA and CH ₃Water (the 60%CH of CN ₃CN brought up to 90% with 8 minutes, brought up to 100% with 1.5 minutes); Detector, UV220254nm.Produce 12mg (30%) (R)-2-phenyl-3-(2-(trifluoromethyl) tetramethyleneimine-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：388[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.178(s，1H)，8.334(s，1H)，8.034-8.031(d，J＝0.9Hz，2H)，7.804-7.777(m，2H)，7.612-7.507(m，3H)，5.710-5.635(m，1H)，3.017-2.928(m，2H)，2.293-2.250(m，1H)，2.018-1.950(m，1H)，1.837-1.800(m，1H)，1.712-1.658(m，1H).

Embodiment 66

3-(6-methoxyl group-3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.1-bromo-2-(brooethyl)-4-anisole

To be dissolved in CCl ₄1-bromo-4-methoxyl group-2-methylbenzene (20g, 100.00mmol, 1.00 equivalents) solution (200mL) adds in the 1000-mL round-bottomed flask.Add NBS (19.58g, 110.00mmol, 1.10 equivalents) and BPO (1.21g, 5.00mmol, 0.05 equivalent) then.Gained solution reflux 7 hours in oil bath.Leach the gained solid.The filtrating vacuum concentration also puts on silicagel column with ethyl acetate/petroleum ether (1: 500) with it.Produce 5.9g (21%) 1-bromo-2-(brooethyl)-4-anisole light yellow solid.

Step 2.3-(2-bromo-5-p-methoxy-phenyl) propionitrile

MeCN (6.2g, 151.22mmol, the 10.00 equivalents) solution that will be dissolved in THF (20mL) adds in the 100mL 3 neck round-bottomed flasks that purge and keep with the nitrogen inert atmosphere.Dropwise stir in-78 ℃ then and add n-BuLi (2.5M is dissolved in hexanone for 15.1mL, 2.50 equivalents).Gained solution stirred 1 hour in-78 ℃ of liquid nitrogen baths.Dropwise stir 1-bromo-2-(brooethyl)-4-anisole (4.2g, 15.11mmol, 1.00 equivalents) solution that adding is dissolved in THF (10mL) in-78 ℃.Gained solution reacted extra 1 hour while stirring, and temperature remains in the liquid nitrogen bath-78 ℃.Add NH then ₄Cl aqueous solution cancellation reaction mixture also extracts with EA (100ml*3).Concentrate organic layer and it is put on silicagel column with PE/EA (10: 1).It is yellow semi-solid to produce 2.29g (63%) 3-(2-bromo-5-p-methoxy-phenyl) propionitrile.

¹H-NMR(300MHz，CDCl ₃，ppm)：δ7.43-7.40(m，1H)，6.84-6.83(d，J＝3Hz，1H)，6.71-6.68(m，1H)，3.78-3.75(d，J＝9Hz，1H)，3.04-2.93(m，2H)，2.67-2.62(t，J＝6Hz，2H).

Step 3.3-(2-bromo-5-p-methoxy-phenyl) third-1-amine

3-(2-bromo-5-p-methoxy-phenyl) propionitrile (2.39g, 10.00mmol, the 1.00 equivalents) solution that will be dissolved in THF (40mL) adds in the 250mL round-bottomed flask.Dropwise stir in 0 ℃ then and add the BH that is dissolved in THF (30mL, 3.00 equivalents) ₃Solution.Gained solution stirred 6 hours in 20 ℃ of oil baths.Then through adding the shrend reaction of going out.Vacuum concentration gained solution.The dilute with water residue.Use 1N sodium hydroxide that the pH regulator of the above-mentioned aqueous solution is 8-9.The aqueous solution that obtains is used the 10x50mL dichloromethane extraction.Merge organic layer, with anhydrous sodium sulfate drying and vacuum concentration.Produce 2.23g (rough) 3-(2-bromo-5-p-methoxy-phenyl) third-1-amine yellow oil.

LC-MS：(ES，m/z)：244[M+H] ⁺

Step 4.3-(3-(2-bromo-5-p-methoxy-phenyl) propyl group is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester

3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (200mg, 0.58mmol, 1.00 equivalents), 3-(2-bromo-5-p-methoxy-phenyl) third-1-amine (1.14g, 2.35mmol, 4.00 equivalents, 50%), n-BuOH (3mL) are added in the 8-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.It is yellow semi-solid to produce 245mg (83%) 3-(3-(2-bromo-5-p-methoxy-phenyl) propyl group is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester.

LC-MS：(ES，m/z)：506[M+H] ⁺

Step 5.3-(6-methoxyl group-3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-(3-(2-bromo-5-p-methoxy-phenyl) propyl group is amino)-2-phenyl quinoxaline-6-carboxylate methyl ester (245mg, 0.49mmol, 1.00 equivalents), Pd ₂(dba) ₃(44.6mg, 0.05mmol, 0.10 equivalent), BINAP (60.4mg, 0.10mmol, 0.20 equivalent), Cs ₂CO3 (479.2mg, 1.47mmol, 3.03 equivalents), two

Alkane (4mL) adds in the 8mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.With ethyl acetate/petroleum ether (1: 70) residue is put on silicagel column.Produce 118mg (57%) 3-(6-methoxyl group-3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：426[M+H] ⁺

Step 6.3-(6-methoxyl group-3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid

(6-methoxyl group-3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (118mg, 0.28mmol, 1.00 equivalents) solution add in the 50mL round-bottomed flask will to be dissolved in the 3-of methyl alcohol (15mL).Dropwise stir sodium hydroxide (55.6mg, 1.39mmol, the 5.00 equivalents) solution that adds water-soluble (2mL) then.Gained solution is stirred overnight in 50 ℃ of oil baths.The mixture of vacuum concentration gained.The dilution of gained solution with water.Use 1N hydrogenchloride that the pH regulator of this aqueous solution is 3-4.Filter and collect the gained solid.Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (100mg): post, SunFire Prep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 60%CH of CN ₃CN brought up to 75% with 8 minutes, brought up to 100% with 1.5 minutes); Detector, UV 220254nm.Produce 57mg (40%) 3-(6-methoxyl group-3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid orange solids.

LC-MS：(ES，m/z)：412[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.30(s，1H)，8.04(d，J＝0.6Hz，2H)，7.71-7.68(m，2H)，7.29-7.27(t，J＝3Hz，3H)，6.64-6.59(m，2H)，6.34-6.30(t，J＝3Hz，1H)，3.74-3.70(t，J＝6Hz，2H)，3.60(s，3H)，2.72-2.67(t，J＝6Hz，2H)，1.96-1.92(t，J＝6Hz，2H).

Embodiment 67

3-(indoline-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.2-(2-bromophenyl) ethamine

2-(2-bromophenyl) acetonitrile (9.8g, 49.99mmol, 1.00 equivalents), THF (50mL) are added in the 500mL 3 neck round-bottomed flasks.0 ℃ is dropwise stirred adding BH then ₃Solution (250mL, 1N is dissolved in THF).Gained solution is stirred overnight at room temperature.Then through adding the 50mL shrend reaction of going out.The mixture of vacuum concentration gained.Gained solution dilutes with 50mL water.With hydrogenchloride (5N) aqueous solution above-mentioned pH value of aqueous solution is adjusted to 2.The said aqueous solution cleans with 3x20mL EA and regulates pH to 11 with sodium hydroxide.Obtained aqueous solution is with the 3x50mL ethyl acetate extraction and merge organic layer and vacuum concentration.Produce 2-(2-bromophenyl) the ethamine brown oil of 5g (50%).

LC-MS：(ES，m/z)：200[M+H] ⁺

Step 2.3-(2-bromobenzene ethylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester:

With 3-chloro-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.50mmol, 1.00 equivalents), 2-(2-bromophenyl) ethamine (300.5mg; 1.51mmol; 3.00 equivalent), salt of wormwood (347.3mg, 2.52mmol, 5.00 equivalents), toluene/DMSO (5/1mL) add in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Gained mixture vacuum concentration also puts on silicagel column with ethyl acetate/petroleum ether (1: 50) with it.Produce 110mg (47%) 3-(2-bromobenzene ethylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：462[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.508-8.503(d，J＝1.5Hz，1H)，8.037-7.936(m，2H)，7.633-7.513(m，6H)，7.281-7.152(m，2H)，7.140-7.083(m，1H)，5.312-5.278(m，1H)，3.912-3.848(m，2H)，3.203-3.157(t，J＝6.9Hz，2H).

Step 3.3-(indoline-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-(2-bromobenzene ethylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester (110mg, 0.24mmol, 1.00 equivalents), Pd ₂(dba) ₃(22mg, 0.02mmol, 0.10 equivalent), BINAP (59.37mg, 0.10mmol, 0.40 equivalent), Cs ₂CO ₃(233mg, 0.71mmol, 3.00 equivalents), 1,4-two

Alkane (5mL) adds in the 10mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Leach the gained solid.The filtrating vacuum concentration also puts on silicagel column with ethyl acetate/petroleum ether (1: 50) with it.Produce 90mg (99%) 3-(indoline-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester orange solids.

LC-MS：(ES，m/z)：382[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.654(s，1H)，8.194-8.119(m，2H)，7.916-7.884(m，2H)，7.779-7.457(m，4H)，7.281-7.228(m，1H)，7.136-7.085(t，J＝7.65Hz，1H)，6.960-6.912(t，J＝7.2Hz，1H)，4.020(s，3H)，3.853-3.798(t，J＝8.25Hz，2H)，3.122-3.068(t，J＝8.1Hz，2H).

Step 4.3-(indoline-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

3-(indoline-1-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (90mg, 0.24mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Sodium hydroxide (47.2mg, 1.18mmol, the 5.00 equivalents) solution that adds water-soluble (2mL) then.Gained solution stirred 2 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Residue dilutes with 20mL water.With hydrogenchloride (1mol/L) aqueous solution above-mentioned pH value of aqueous solution is adjusted to 4-5.Filter and collect the gained solid.Produce 80mg (92%) 3-(indoline-1-yl)-2-phenyl quinoxaline-6-carboxylic acid orange solids.

LC-MS：(ES，m/z)：368[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.362(s，1H)，8.127-7.983(m，2H)，7.868-7.855(d，J＝3.9Hz，2H)，7.454(s，3H)，7.261-7.175(m，2H)，7.010-6.961(t，J＝7.35Hz，1H)，6.849-6.801(t，J＝7.2Hz，1H)，3.781-3.730(t，J＝7.65Hz，2H)，3.043-2.992(t，J＝7.65Hz，2H).

Embodiment 68

3-(2; 3-dihydrobenzo [b] [1,4] piperazine-4-yl)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.2-(2-bromobenzene oxygen) acetonitrile

With 2-bromophenol (5.1g, 29.48mmol, 1.00 equivalents), 2-bromoacetonitrile (5.3g, 44.19mmol, 1.50 equivalents), salt of wormwood (8g, 57.97mmol, 2.00 equivalents), N, dinethylformamide (20mL) adds in the 50-mL round-bottomed flask.Gained solution is stirred overnight in 60 ℃ of oil baths.Gained solution dilutes with 5x50mL EA.Clean organic layer with 50mL water.Collected organic layer and vacuum concentration.With ethyl acetate/petroleum ether (1: 100) residue is put on silicagel column.Produce 6g (96%) 2-(2-bromobenzene oxygen) acetonitrile brown solid.

LC-MS(ES，m/z)：212[M+H] ⁺

Step 2.2-(2-bromobenzene oxygen) ethamine

2-(2-bromobenzene oxygen) acetonitrile (5.63g, 26.68mmol, the 1.00 equivalents) solution that will be dissolved in THF (20mL) adds in the 500mL 3 neck round-bottomed flasks that purge and keep with the nitrogen inert atmosphere.Dropwise stir in 0 ℃ then and add the BH that is dissolved in THF (143mL, 5.30 equivalents) ₃Stirred overnight is also gone out with (10ml) shrend in 20 ℃ of oil baths of gained solution.Gained mixture vacuum concentration and dilute with water.Using 1N sodium hydroxide is 10 with above-mentioned aqueous solution pH regulator, and uses the 6x50mL dichloromethane extraction.Merge organic layer and vacuum concentration.Produce 2-(2-bromobenzene oxygen) the ethamine light brown oil of 5.67g (rough).

LC-MS：(ES，m/z)：216[M+H] ⁺

Step 3.3-(2-(2-bromobenzene oxygen) ethylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester

3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (150mg, 0.44mmol, 1.00 equivalents), 2-(2-bromobenzene oxygen) ethamine (750mg, 1.74mmol, 3.98 equivalents, 50%), n-BuOH (2mL) are added in the 8mL pressure-pot reactor drum.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With PE/EA (10: 1) residue is put on silicagel column.Produce 163.9mg (rough) 3-(2-(2-bromobenzene oxygen) ethylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow solid.

Step 4.3-(2; 3-dihydrobenzo [b] [1,4]

piperazine-4-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-(2-(2-bromobenzene oxygen) ethylamino)-2-phenyl quinoxaline-6-carboxylate methyl ester (363.9mg, 0.76mmol, 1.00 equivalents), Pd ₂(dba) ₃(70.2mg, 0.08mmol, 0.10 equivalent), BINAP (189.8mg, 0.31mmol, 0.40 equivalent), Cs ₂CO ₃(746.1mg, 2.29mmol, 3.00 equivalents), 1,4-two

Alkane (5mL) adds in the 20mL ST that purges and keep with the nitrogen inert atmosphere.Stirred overnight, vacuum concentration then in 100 ℃ of oil baths of the solution that obtains.With ethyl acetate/petroleum ether (1: 50) residue is put on silicagel column.Produce 166.8mg (44%) 3-(2; 3-dihydrobenzo [b] [1,4]

piperazine-4-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS：(ES，m/z)：398[M+H] ⁺

Step 5.3-(2; 3-dihydrobenzo [b] [1,4]

piperazine-4-yl)-2-phenyl quinoxaline-6-carboxylic acid

To be dissolved in the 3-(2 of methyl alcohol (15mL); 3-dihydrobenzo [b] [1; 4]

piperazine-4-yl)-2-phenyl quinoxaline-6-carboxylate methyl ester (166.8mg; 0.34mmol, 1.00 equivalents, 80%) and solution adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (84mg, 2.10mmol, the 5.00 equivalents) solution that adds water-soluble (1.5mL) then.Gained solution is stirred overnight in 50 ℃ of oil baths.Use the 1N hydrochloride aqueous solution that the pH regulator of the above-mentioned aqueous solution is 3-4 and vacuum concentration.Through preparation HPLC with following condition (1#-Waters 2767-2) purifying crude product (100mg): post, SunFire Prep C18,5um, 19*150mm; Moving phase contains 0.05%TFA and CH ₃Water (the 20%CH of CN ₃CN brought up to 35% with 8 minutes, brought up to 70% with 8 minutes, brought up to 100% with 1.5 minutes); Detector, uv 220 and 254nm.Produce 40mg (31%) 3-(2; 3-dihydrobenzo [b] [1,4]

piperazine-4-yl)-2-phenyl quinoxaline-6-carboxylic acid orange solids.

LC-MS：(ES，m/z)：384[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.21(s，1H)，8.34(s，1H)，8.16-8.09(m，2H)，7.91-7.88(m，2H)，7.42-7.40(t，J＝6Hz，3H)，6.91-6.88(d，J＝9Hz，1H)，6.77-6.73(t，J＝6Hz，2H)，6.59-6.53(m，1H)，4.29-4.28(d，J＝3Hz，2H)，3.67(s，2H).

Embodiment 69

3-(sec.-propyl (methyl) amino)-2-(3-p-methoxy-phenyl) quinoxaline-6-carboxylic acid

Step 1.3-(sec.-propyl (methyl) amino)-2-(3-p-methoxy-phenyl) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (120mg, 0.41mmol, 1.00 equivalents), 3-anisole ylboronic acid (188mg, 1.23mmol, 3.00 equivalents), Pd (PPh ₃) ₄(94mg, 0.08mmol, 0.20 equivalent), K ₃PO ₄(346mg, 1.64mmol, 4.00 equivalents), 1,4-two

Alkane (4mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 30) residue is put on silicagel column.Produce 50mg (33%) 3-(sec.-propyl (methyl) amino)-2-(3-p-methoxy-phenyl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：366[M+H] ⁺

Step 2.3-(sec.-propyl (methyl) amino)-2-(3-p-methoxy-phenyl) quinoxaline-6-carboxylic acid

3-(sec.-propyl (methyl) amino)-2-(3-p-methoxy-phenyl) quinoxaline-6-carboxylate methyl ester (50mg, 0.14mmol, 1.00 equivalents), methyl alcohol (10mL), sodium hydroxide (27.4mg, 0.69mmol, 5.00 equivalents), water (2mL) are added in the 50mL round-bottomed flask.Gained solution stirred 2 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Gained solution dilutes with 20mL water.(1mol/L) is adjusted to 4-5 with this pH value of aqueous solution with hydrogenchloride.Filter and collect the gained solid.Produce 20mg (41%) 3-(sec.-propyl (methyl) amino)-2-(3-p-methoxy-phenyl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：352[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.250(s，1H)，7.931(s，2H)，7.382-7.250(m，3H)，7.076(s，1H)，4.218(s，1H)，3.827(s，3H)，2.699(s，3H)，1.030-1.048(d，J＝5.4Hz，6H).

Embodiment 70

2-(3-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

Step 1.2-(3-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (110mg, 0.38mmol, 1.00 equivalents), 3-fluorophenyl boric acid (157.4mg, 1.12mmol, 3.00 equivalents), Pd (PPh ₃) ₄(86.5mg, 0.07mmol, 0.20 equivalent), K ₃PO ₄(318mg, 1.51mmol, 4.00 equivalents), 1,4-two

Alkane (4mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 30) residue is put on silicagel column.Produce 75mg (57%) 2-(3-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：354[M+H] ⁺

Step 2.2-(3-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

2-(3-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (75mg, 0.21mmol, 1.00 equivalents), methyl alcohol (15mL), sodium hydroxide (42mg, 1.05mmol, 4.94 equivalents), water (2mL) are added in the 50mL round-bottomed flask.Gained solution stirred 2 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Gained solution dilutes with 20mL water.With hydrogenchloride (1mol/L) aqueous solution above-mentioned pH value of aqueous solution is adjusted to 4-5.Filter and collect the gained solid.Through preparation HPLC with following condition (1#-Waters 2767-2) purifying crude product (70mg): post, SunFire Prep C18,5um, 19*150mm; Moving phase contains 0.05%TFA and CH ₃Water (the 50%CH of CN ₃CN brought up to 80% with 8 minutes, brought up to 100% with 1.5 minutes); Detector, uv 220 and 254nm.Produce 20mg (27%) 2-(3-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：340[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ8.266(s，1H)，7.984-7.924(m，2H)，7.689-7.623(m，2H)，7.596-7.550(m，1H)，7.378-7.316(m，1H)，4.216-4.130(m，1H)，2.676(s，3H)，1.053-1.031(d，J＝6.6Hz，6H).

Embodiment 71

2-(2-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

With 2-chloro-3-(isopropyl methyl) amino) quinoxaline carboxylic acid's methyl esters (80mg, 0.27mmol, 1.00 equivalents), 2-fluorophenyl boric acid (115mg, 0.82mmol, 3.00 equivalents), Pd (PPh ₃) ₄(62.9mg, 0.05mmol, 0.20 equivalent), 1,4-two

Alkane (3mL), K ₃PO ₄(231mg, 1.09mmol, 4.00 equivalents) add in the 10-mL round-bottomed flask.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.Gained solution is used 40mL DCM: MeOH=10: 1 dilution.Leach solid.The filtrating vacuum concentration.Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (100mg): post, SunFire Prep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 50%CH of CN ₃CN brought up to 80% with 8 minutes, brought up to 100% with 1.5 minutes); Detector, UV 220 and 254nm.Produce 40mg (43%) 2-(2-fluorophenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：340[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ13.250(s，1H)，8.268(s，1H)，7.945(s，1H)，7.776-7.731(m，1H)，7.602-7.538(m，1H)，7.424-7.342(m，2H)，4.299-4.212(m，1H)，2.636(s，3H)，1.017-0.995(d，J＝6.6Hz，6H).

Embodiment 72

3-(cyclopentyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

Step 1.3-(encircling penta amino)-2-phenyl quinoxaline-6-carboxylate methyl ester

With 3-bromo-2-phenyl quinoxaline-6-carboxylate methyl ester (200mg, 0.58mmol, 1.00 equivalents), NSC 32389 (246.8mg, 2.90mmol, 5.00 equivalents) and n-BuOH (2mL) add in the 8-mL ST.Gained solution stirred 4 hours in 100 ℃ of oil baths.The reaction mixture vacuum concentration.Through silica gel column chromatography purifying residue, produce 214.1mg (rough) 3-(encircling penta amino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow oil with ethyl acetate/petroleum ether (1: 50).

LC-MS(ES，m/z)：348[M+H] ⁺

Step 2.3-(cyclopentyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylate methyl ester

3-(encircling penta amino)-2-phenyl quinoxaline-6-carboxylate methyl ester (214.1mg, 0.62mmol, 1.00 equivalents) solution that will be dissolved in THF (10mL) adds in the 50mL round-bottomed flask that purges and keep with the nitrogen inert atmosphere.Dropwise stir in 0 ℃ then and add sodium hydride (246.8mg, 6.17mmol, 10.00 equivalents, 60%).Stirring at room gained solution 1 hour.Dropwise stir in 0 ℃ then and add the CH that is dissolved in THF (2mL) ₃I (1.75g, 12.32mmol, 20.00 equivalents) solution.Gained solution is stirred overnight at room temperature.Then through adding the shrend reaction of going out.The mixture of vacuum concentration gained.Produce 200mg (slightly) 3-(cyclopentyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS：(ES，m/z)：362[M+H] ⁺

Step 3.3-(cyclopentyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid

3-(cyclopentyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylate methyl ester (200mg, 0.55mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (110.8mg, 2.77mmol, the 5.00 equivalents) solution that adds water-soluble (3mL) then.Gained solution stirred 3 hours in 50 ℃ of oil baths.Use 1N hydrogenchloride that the pH regulator of this aqueous solution is 3-4.Filtration is collected the gained solid and is washed with ether.Produce 56mg (29%) 3-(cyclopentyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：348[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.15-13.12(t，J＝3Hz，1H)，8.26(s，1H)，7.94(d，J＝0.3Hz，2H)，7.85-7.83(d，J＝6Hz，2H)，7.56-7.48(m，3H)，4.31-4.27(t，J＝6Hz，1H)，2.69(s，3H)，1.67-1.54(m，6H)，1.40-1.38(d，J＝6Hz，2H).

Embodiment 73

Step 1.3-(sec.-propyl (methyl) amino)-2-(2-p-methoxy-phenyl) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (290mg, 0.99mmol, 1.00 equivalents), 2-anisole ylboronic acid (453.5mg, 2.96mmol, 3.00 equivalents), Pd (PPh ₃) ₄(228mg, 0.20mmol, 0.20 equivalent), K ₃PO ₄(837mg, 3.97mmol, 4.00 equivalents), 1,4-two Alkane (4mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Gained mixture vacuum concentration also puts on silicagel column with ethyl acetate/petroleum ether (1: 40) with it.Produce 100mg (28%) 3-(sec.-propyl (methyl) amino)-2-(2-p-methoxy-phenyl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：366[M+H] ⁺

3-(sec.-propyl (methyl) amino)-2-(4-p-methoxy-phenyl) quinoxaline-6-carboxylate methyl ester (110mg, 0.30mmol, 1.00 equivalents), methyl alcohol (15mL), sodium hydroxide (60mg, 1.50mmol, 5.00 equivalents) and water (2mL) are added in the 50mL round-bottomed flask.Gained solution stirred 5 hours in 50 ℃ of oil baths.Gained mixture vacuum concentration also dilutes with 20ml water.(1mol/L) is adjusted to 4-5 with above-mentioned pH value of aqueous solution with hydrochloride aqueous solution.Filter and collect the gained solid.Produce 50mg (46%) 3-(sec.-propyl (methyl) amino)-2-(4-p-methoxy-phenyl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：352[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.099(s，1H)，8.218(s，1H)，7.882-7.879(d，J＝0.9Hz，2H)，7.532-7.447(m，2H)，7.161-7.090(m，2H)，4.449-4.405(m，1H)，3.744(s，3H)，2.565(s，3H)，1.002-0.980(d，J＝6.6Hz，6H).

Embodiment 74

(S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylic acid

Step 1.4-(1-(4-fluorophenyl)-2-methoxyl group-2-oxo ethylamino)-3-nitrobenzoic acid methyl esters

With 4-fluoro-3-nitrobenzoic acid methyl esters (15.4g; 77.78mmol, 1.00 equivalents), N, dinethylformamide (100mL), 2-amino-2-(4-fluorophenyl) methyl acetate hydrochloride (20.4g; 93.15mmol; 1.20 equivalent) and DIEA (50.2g, 389.15mmol, 5.00 equivalents) add in the 250-mL round-bottomed flask.React on stirred overnight in 35 ℃ of oil baths.Gained solution is with the dilution of 500ml water and filter collection gained solid.Produce 15g (53%) 4-(1-(4-fluorophenyl)-2-methoxyl group-2-oxoethyl is amino)-3-nitrobenzoic acid methyl esters yellow solid.

Step 2.2-(4-fluorophenyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate methyl ester

4-(1-(4-fluorophenyl)-2-methoxyl group-2-oxoethyl is amino)-3-nitrobenzoic acid methyl esters (3.5g, 9.67mmol, 1.00 equivalents), methyl alcohol (50mL) and carbon are carried palladium (10%) (500mg) to add in the 100mL round-bottomed flask.Hydrogen imports reaction and stirred overnight in 30 ℃ of oil baths.Leach solid then and the vacuum concentration of will filtrating.Produce 2.6g (90%) 2-(4-fluorophenyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate methyl ester light yellow solid.

LC-MS：(ES，m/z)：301[M+H] ⁺

Step 3.3-chloro-2-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester

With 2-(4-fluorophenyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate methyl ester (1.2g, 4.00mmol, 1.00 equivalents), POCl ₃(12.2g, 80.26mmol, 20.00 equivalents), N, accelerine (4.9g, 40.50mmol, 10.00 equivalents) adds in the 100mL round-bottomed flask.Stirred overnight in 110 ℃ of oil baths of the solution that obtains.Gained mixture vacuum concentration also dilutes with 50ml water.(4mol/L) is adjusted to 7 with this pH value of aqueous solution with sodium hydrogencarbonate.Gained mixture vacuum concentration also passes through the silica gel column chromatography purifying with ethyl acetate/petroleum ether (1: 40).Produce 0.5g (40%) 3-chloro-2-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester white solid.

LC-MS：(ES，m/z)：317[M+H] ⁺

¹H-NMR(300MHz，CDCl ₃，ppm)：δ8.785-8.779(d，J＝1.8Hz，1H)，8.433-8.398(m，1H)，8.214-8.185(d，J＝8.7Hz，1H)，7.973-7.926(m，2H)，7.265(d，1H)，4.052(s，3H).

Step 4. (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl) quinoxaline-6-butyl carboxylate

3-chloro-2-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester (150mg, 0.47mmol, 1.00 equivalents), (S)-2-crassitude (403mg, 4.74mmol, 9.99 equivalents), fourth-1-alcohol (2mL) are added in the 10-mL ST.Gained solution is stirred overnight in 110 ℃ of oil baths.The mixture of vacuum concentration gained.Produce 150mg (rough) (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl) quinoxaline-6-butyl carboxylate yellow solid.

LC-MS：(ES，m/z)：408[M+H] ⁺

Step 5. (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylic acid

(S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl) quinoxaline-6-butyl carboxylate (150mg, 0.37mmol, 1.00 equivalents), methyl alcohol (15mL), sodium hydroxide (74mg, 1.85mmol, 5.02 equivalents), water (2mL) are added in the 10mL ST.Gained solution stirred 2 hours in 50 ℃ of oil baths.Gained mixture vacuum concentration also dilutes with 20ml water.(1mol/L) is adjusted to 4-5 with above-mentioned pH value of aqueous solution with hydrochloride aqueous solution.Filter and collect the gained solid.Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (150mg): post, SunFire Prep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 60%CH of CN ₃CN brought up to 75% with 8 minutes, brought up to 100% with 1.5 minutes); Detector, UV 220254nm.Produce 60mg (46%) (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：352[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.161(s，1H)，8.243-8.240(d，J＝0.9Hz，1H)，7.941-7.770(m，4H)，7.395-7.336(t，J＝8.85Hz，2H)，4.242-4.221(m，1H)，3.018-2.936(m，2H)，2.126(s，1H)，1.767(s，1H)，1.336-1.316(d，J＝6.0Hz，3H).

Embodiment 75

2-(4-fluorophenyl)-3-(piperidines-1-yl) quinoxaline-6-butyl carboxylate

Step 1.2-(4-fluorophenyl)-3-(piperidines-1-yl) quinoxaline-6-butyl carboxylate

3-chloro-2-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester (150mg, 0.47mmol, 1.00 equivalents), piperidines (403mg, 4.74mmol, 10.00 equivalents), fourth-1-alcohol (2mL) are added in the 10-mL ST.Stirred overnight in 110 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.Produce 150mg (rough) 2-(4-fluorophenyl)-3-(piperidines-1-yl) quinoxaline-6-butyl carboxylate yellow solid.

LC-MS(ES，m/z)：408[M+H] ⁺

Step 2.2-(4-fluorophenyl)-3-(piperidines-1-yl) quinoxaline-6-carboxylic acid

2-(4-fluorophenyl)-3-(piperidines-1-yl) quinoxaline-6-butyl carboxylate (150mg, 0.37mmol, 1.00 equivalents), methyl alcohol (15mL), sodium hydroxide (74mg, 1.85mmol, 5.02 equivalents), water (2mL) are added in the 50mL round-bottomed flask.Gained solution stirred 2 hours in 50 ℃ of oil baths.Gained mixture vacuum concentration also dilutes with 20ml water.(1mol/L) is adjusted to 4-5 with above-mentioned pH value of aqueous solution with hydrochloride aqueous solution.Filter and collect the gained solid.Through preparation HPLC with following condition (Gilson preparation HPLC (peak pressure: 8MPa)) purifying crude product (150mg): post, SunFire Prep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 70%CH of CN ₃CN brought up to 77.5% with 6 minutes, brought up to 100% with 0.1 minute again, kept 1.9 minutes 100%); Detector, UV 220NMnm.Produce 70mg (52%) 2-(4-fluorophenyl)-3-(piperidines-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：352[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)δ13.206(s，1H)，8.275(s，1H)，8.085-7.943(m，4H)，7.416-7.357(t，J＝5.9Hz，2H)，3.198(s，4H)，1.533(s，6H).

Embodiment 76

3-(azepan-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid

Step 1.3-(azepan-1-yl)-2-(4-fluorophenyl) quinoxaline-6-butyl carboxylate

3-chloro-2-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester (150mg, 0.47mmol, 1.00 equivalents), azepan (470mg, 4.75mmol, 10.00 equivalents), fourth-1-alcohol (2mL) are added in the 10-mL ST.Stirred overnight in 110 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.Produce 150mg (rough) 3-(azepan-1-yl)-2-(4-fluorophenyl) quinoxaline-6-butyl carboxylate yellow solid.

LC-MS(ES，m/z)：422[M+H] ⁺

Step 2.3-(azepan-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid

3-(azepan-1-yl)-2-(4-fluorophenyl) quinoxaline-6-butyl carboxylate (150mg, 0.36mmol, 1.00 equivalents), methyl alcohol (15mL), sodium hydroxide (71mg, 1.77mmol, 4.98 equivalents), water (2mL) are added in the 50mL round-bottomed flask.Gained solution stirred 2 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Gained solution dilutes with 20mL water.(1mol/L) is adjusted to 4-5 with above-mentioned pH value of aqueous solution with hydrochloride aqueous solution.Filter and collect the gained solid.Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (150mg): post, XbridgePrep Shield RP 18,5um, 19*150mm; Moving phase contains 0.05%TFA and CH ₃Water (the 60%CH of CN ₃CN brought up to 90% with 8 minutes, brought up to 100% with 1.5 minutes); Detector, UV 220 254nm.Produce 80mg (61%) 3-(azepan-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：366[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)：δ13.188(s，1H)，8.225(s，1H)，7.932-7.709(m，4H)，7.388-7.329(t，J＝8.85Hz，2H)，3.343-3.334(m，4H)，1.630(s，4H)，1.415(s，4H).

Embodiment 77

2-(benzo [d] [1,3] dioxo-5-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

Step 1.2-(benzo [d] [1,3] dioxo-5-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (160mg, 0.55mmol, 1.00 equivalents), benzo [d] [1,3] dioxo-5-ylboronic acid (271mg, 1.63mmol, 3.00 equivalents, PCy ₃(76mg, 0.27mmol, 0.40 equivalent), Pd ₂(dba) ₃(130mg, 0.14mmol, 0.20 equivalent), K ₃PO ₄(462mg, 2.18mmol, 4.00 equivalents) and 1,4-two

Alkane (3mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 4) residue is put on silicagel column.Produce 150mg (72%) 2-(benzo [d] [1,3] dioxo-5-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS-PH：(ES，m/z)：380[M+H] ⁺

Step 2.2-(benzo [d] [1,3] dioxo-5-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

With 2-(benzo [d] [1; 3] dioxo-5-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (150mg, 0.40mmol, 1.00 equivalents), methyl alcohol (15mL), sodium hydroxide (79mg; 1.98mmol, 4.99 equivalents) and the solution of water (2mL) add in the 50mL round-bottomed flask.Gained solution stirred 2 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Gained solution dilutes with 20mL water.(1mol/L) is adjusted to 4-5 with this pH value of aqueous solution with hydrogenchloride.Filter and collect the gained solid.Produce 60mg (40%) 2-(benzo [d] [1,3] dioxo-5-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：366[M+H] ⁺

¹H?NMR(300MHz，DMSO，ppm)δ13.035(s，1H)，8.238(s，1H)，7.946-7.895(m，2H)，7.412-7.388(m，2H)，7.075-7.055(d，J＝6.0Hz，1H)，6.123(s，2H)，4.233-4.183(m，1H)，2.693(s，3H)，1.060-1.043(d，J＝5.1Hz，6H).

Embodiment 78

2-(4-fluorophenyl)-3-(3-(methoxymethyl) piperidines-1-yl) quinoxaline-6-carboxylic acid

Step 1.2-(4-fluorophenyl)-3-(3-(methoxymethyl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester

3-(methoxymethyl) piperidine hydrochlorate (170mg, 1.03mmol, the 2.00 equivalents) solution and the sodium methylate (128mg, 2.37mmol, 5.00 equivalents) that will be dissolved in methylene dichloride (7mL) add in the 50mL ST.Stirring at room gained solution 3 hours.Leach solid.Gained mixture vacuum concentration and add to 3-chloro-2-(4-fluorophenyl) quinoxaline is arranged-the 8mL ST of 6-carboxylate methyl ester (150mg, 0.47mmol, 1.00 equivalents) and DMSO (4mL) in.100 ℃ of stirred overnight of the mixture that obtains.The adding shrend is gone out and is reacted and filtration collection gained solid.Through this residue of purification by silica gel column chromatography with PE/EA (50: 1).Produce 179.9mg (88%) 2-(4-fluorophenyl)-3-(3-(methoxymethyl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：410[M+H] ⁺

Step 2.2-(4-fluorophenyl)-3-(3-(methoxymethyl) piperidines-1-yl) quinoxaline-6-carboxylic acid

2-(4-fluorophenyl)-3-(3-(methoxymethyl) piperidines-1-yl) quinoxaline-6-carboxylate methyl ester (152.3mg, 0.37mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (44.7mg, 1.12mmol, the 3 equivalents) solution that adds water-soluble (1.5mL) then.Gained solution stirred 4 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.The dilution of gained solution with water.Use 1N hydrogenchloride that the pH regulator of this aqueous solution is 3-4.Filter to collect the gained solid and through preparation HPLC with following condition (Agilent preparation HPLC (UV-guiding)) purifying crude product (240mg): post, SunFire Prep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 45%CH of CN ₃CN brought up to 60% with 8 minutes, kept 5 minutes 60%, brought up to 100% with 0.1 minute again, 100% maintenance 1.4 minutes); Detector, uv 220 and 254nm.Produce 89mg (61%) 2-(4-fluorophenyl)-3-(3-(methoxymethyl) piperidines-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：396[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)13.22(s，1H)，8.29-8.28(d，J＝3Hz，1H)，8.05-7.95(m，4H)，7.41-7.35(t，J＝9H，2H)，3.77-3.73(d，J＝12Hz，1H)，3.59-3.55(d，J＝12Hz，1H)，3.19-3.07(m，5H)，2.77-2.70(t，J＝10.5Hz，1H)，2.60-2.57(d，J＝9Hz，1H)，1.72(s，1H)，1.67-1.57(m，3H)，1.50-1.49(m，1H).

Embodiment 79

3-(3,3-lupetidine-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid

Step 1.3-(3,3-lupetidine-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester

With 3-chloro-2-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester (150mg, 0.47mmol, 1.00 equivalents), 3,3-lupetidine (107mg, 0.95mmol, 2.00 equivalents), DMSO (2mL) add in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Gained solution dilutes with 20mL water.Filter and collect the gained solid.Through this residue of purification by silica gel column chromatography with ethyl acetate/petroleum ether (1: 40).Produce 120mg (64%) 3-(3,3-lupetidine-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：394[M+H] ⁺

Step 2.3-(3,3-lupetidine-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid

With 3-(3; 3-lupetidine-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester (120mg, 0.31mmol, 1.00 equivalents), methyl alcohol (15mL), sodium hydroxide (61mg; 1.52mmol, 4.99 equivalents) and the solution of water (2mL) add in the 50mL round-bottomed flask.Gained solution stirred 2 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Gained solution dilutes with 20mL water.(1mol/L) is adjusted to 4-5 with this pH value of aqueous solution with hydrogenchloride.Filter and collect the gained solid.Produce 60mg (52%) 3-(3,3-lupetidine-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：380[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)δ8.291-8.290(d，J＝0.3Hz，1H)，7.992-7.957(m，4H)，7.435-7.391(t，J＝6.6Hz，2H)，3.067-3.039(m，4H)，1.466(s，2H)，1.357-1.329(m，2H)，0.905(s，6H).

Embodiment 80

2-(4-fluorophenyl)-3-(3-methyl piperidine-1-yl) quinoxaline-6-carboxylic acid

is with 3-chloro-2-(4-fluorophenyl) quinoxaline-6-carboxylate methyl ester (200mg; 0.63mmol; 1.00 3-methyl piperidine (313mg equivalent); 3.16mmol, 5.00 equivalents), DMSO (3mL) adds in the 8-mL ST.Stirred overnight in 110 ℃ of oil baths of the solution that obtains.Then through adding the shrend reaction of going out.Use 1N hydrogenchloride that the pH regulator of this aqueous solution is 3-4.Filter and collect the gained solid.Through preparation HPLC with following condition (1#-UV1-SHIMADZU-SPD-20A) purifying crude product (240mg): post, SunFire Prep C18,5um, 19*150mm; Moving phase contains 0.05%TFA and CH ₃Water (the 30%CH of CN ₃CN brought up to 100% with 8 minutes, kept 1.5 minutes 100%, was reduced to 30% with 1 minute); Detector, Gilson UV detector 220nm.Produce 75mg (32%) 2-(4-fluorophenyl)-3-(3-methyl piperidine-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：366[M+H] ⁺

¹H?NMR(300MHz，DMSO，ppm)13.24(s，1H)，8.28(s，1H)，8.05-7.94(m，4H)，7.41-7.35(t，J＝9Hz，2H)，3.64-3.60(d，J＝12Hz，2H)，2.70-2.51(m，1H)，2.50-2.37(m，1H)，1.75-1.46(m，5H)，1.06-1.05(d，J＝3Hz，3H).

Embodiment 81

2-(2,3-dihydrobenzo [b] [1,4] dioxine-6-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (150mg, 0.51mmol, 1.00 equivalents), 2,3-dihydrobenzo [b] [1,4] dioxine-6-ylboronic acid (184mg, 1.02mmol, 2.00 equivalents), Pd (PPh ₃) ₂Cl ₂(36mg, 0.05mmol, 0.10 equivalent), K ₃PO ₄(433mg, 2.04mmol, 3.99 equivalents), 1,4-two

Alkane/H ₂O (4/1mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.Through this residue of purification by silica gel column chromatography with methylene chloride (10: 1).Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (70mg): post, SunFirePrep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 48%CH of CN ₃CN brought up to 68% with 8 minutes, brought up to 100% with 2 minutes); Detector, UV 220254nm.Produce 20mg (10%) 2-(2,3-dihydrobenzo [b] [1,4] dioxine-6-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：380[M+H] ⁺

¹H?NMR(300MHz，DMSO，ppm)δ13.109(s，1H)，8.233(s，1H)，7.949-7.885(m，2H)，7.402-7.356(m，2H)，7.008-6.980(d，J＝8.4Hz，1H)，4.315(s，4H)，4.251-4.163(m，1H)，2.729-2.693(d，J＝10.8Hz，3H)，1.061-1.039(d，J＝6.6Hz，6H).

Embodiment 82

3-(sec.-propyl (methyl) amino)-2-(4-(methylsulfonyl) phenyl) quinoxaline-6-carboxylic acid

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (150mg, 0.51mmol, 1.00 equivalents), 4-(methylsulfonyl) phenyl-boron dihydroxide (205mg, 1.02mmol, 2.00 equivalents), Pd (PPh ₃) ₄(59mg, 0.05mmol, 0.10 equivalent), K ₃PO ₄(433mg, 2.04mmol, 3.99 equivalents) and 1,4-two

Alkane/H ₂O (4/2mL) adds in the 10-mL round-bottomed flask.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.Through this residue of purification by silica gel column chromatography with methylene chloride (1: 30).Through preparation HPLC with following condition (1#-Waters 2767-2) purifying crude product (60mg): post, SunFire Prep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 35%CH of CN ₃CN brought up to 57% with 9 minutes, brought up to 100% with 0.1 minute, kept 0.9 minute 100%); Detector, uV220 and 254nm.Produce 25mg (12%) 3-(sec.-propyl (methyl) amino)-2-(4-(methylsulfonyl) phenyl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：400[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)δ13.198(s，1H)，8.280(s，1H)，8.091(s，4H)，7.997-7.968(d，J＝8.7Hz，2H)，4.232-4.189(m，1H)，3.329-3.292(d，J＝11.1Hz，3H)，2.653(s，3H)，1.077-1.055(d，J＝6.6Hz，6H).

Embodiment 83

2-(benzo [d] [1,3] dioxo-5-yl)-3-((S)-2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylic acid

Step 1. (S)-1-benzyl-3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydro-quinoxaline-6-carboxylate methyl ester

With 1-benzyl-3-chloro-2-oxo-1,2-dihydro-quinoxaline-6-carboxylate methyl ester (3g, 9.15mmol, 1.00 equivalents), (S)-2-crassitude (1.55g, 18.24mmol, 2.00 equivalents), DMSO (16mL) add in the 50mL round-bottomed flask.Gained solution is stirred overnight in 80 ℃ of oil baths.Vacuum concentration gained solution.Through this residue of purification by silica gel column chromatography with ethyl acetate/petroleum ether (1: 20).Produce 2.2g (64%) (S)-1-benzyl-3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydro-quinoxaline-6-carboxylate methyl ester light yellow solid.

LC-MS：(ES，m/z)：378[M+H] ⁺

Step 2. (S)-3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydro-quinoxaline-6-carboxylate methyl ester

To be dissolved in (S)-1-benzyl-3-(2-methylpyrrolidin-1-the yl)-2-oxo-1 of methylene dichloride (100mL), 2-dihydro-quinoxaline-6-carboxylate methyl ester (2.2g, 5.84mmol, 1.00 equivalents) solution adds in the 250mL round-bottomed flask.Add AlCl then in batches ₃(7.7g, 58.33mmol, 10.00 equivalents).Gained solution is stirred overnight in 30 ℃ of oil baths.Vacuum concentration gained solution.With methylene chloride (1: 100) residue is put on silicagel column.Produce 900mg (53%) (S)-3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydro-quinoxaline-6-carboxylate methyl ester brown solid.

LC-MS：(ES，m/z)：288[M+H] ⁺

Step 3. (S)-2-chloro-3-(2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylate methyl ester

With (S)-3-(2-methylpyrrolidin-1-yl)-2-oxo-1; 2-dihydro-quinoxaline-6-carboxylate methyl ester (900mg; 3.14mmol, 1.00 equivalents), toluene (20mL), THIONYL CHLORIDE 97 (11.2g, 94.12mmol; 30.00 equivalent), N, dinethylformamide (4mL) solution adds in the 100-mL round-bottomed flask.Gained solution reflux 3 hours in oil bath.The mixture of vacuum concentration gained.Through this residue of purification by silica gel column chromatography with ethyl acetate/petroleum ether (1: 50).Produce 143mg (13%) (S)-2-chloro-3-(2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS：(ES，m/z)：306[M+H] ⁺

Step 4.2-(benzo [d] [1,3] dioxo-5-yl)-3-((S)-2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylate methyl ester

With (S)-2-chloro-3-(2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylate methyl ester (89.2mg, 0.29mmol, 1.00 equivalents), benzo [d] [1,3] dioxo-5-ylboronic acid (97.1mg, 0.58mmol, 2.00 equivalents), Pd (PPh ₃) ₄(33.7mg, 0.03mmol, 0.10 equivalent), K ₃PO ₄(248mg, 1.17mmol, 4.00 equivalents), two

In the 8-mL ST that alkane (4mL) adding nitrogen inert atmosphere purges and keeps.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.Vacuum concentration gained solution.Through this residue of purification by silica gel column chromatography with PE/EA (50: 1).Produce 94mg (82%) 2-(benzo [d] [1,3] dioxo-5-yl)-3-((S)-2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylate methyl ester yellow oil.

LC-MS：(ES，m/z)：392[M+H] ⁺

Step 5.2-(benzo [d] [1,3] dioxo-5-yl)-3-((S)-2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylic acid

2-(benzo [d] [1,3] dioxo-5-yl)-3-((S)-2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylate methyl ester (94mg, 0.24mmol, 1.00 equivalents) solution that will be dissolved in methyl alcohol (15mL) adds in the 50mL round-bottomed flask.Dropwise stir sodium hydroxide (58.9mg, 1.47mmol, the 5.00 equivalents) solution that adds water-soluble (3mL) then.Gained solution stirred 5 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.The dilution of gained solution with water.Use the 1N hydrochloride aqueous solution that the pH regulator of the above-mentioned aqueous solution is 3-4.Filter and collect the gained solid.Through preparation HPLC with following condition (1#-Waters 2767-2) purifying crude product (100mg): post, SunFire Prep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 10%CH of CN ₃CN brought up to 80% with 8.5 minutes, kept 1 minute 80%, brought up to 100% with 0.1 minute, 100% maintenance 0.8 minute); Detector, UV 220 and 254nm.Produce 40mg (44%) 2-(benzo [d] [1,3] dioxo-5-yl)-3-((S)-2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：378[M+H] ⁺

¹H?NMR(400MHz，DMSO，ppm)13.05(s，1H)，8.23(s，1H)，7.91-7.90(t，J＝2Hz，2H)，7.30-7.23(t，J＝14Hz，2H)，7.07-7.05(d，J＝8Hz，1H)，6.13-6.12(d，J＝4Hz，2H)，4.27-4.22(m，1H)，3.16-3.10(m，1H)，3.02-2.98(m，1H)，2.13(s，1H)，1.79(s，1H)，1.62-1.50(m，2H)，1.33-1.24(m，3H).

Embodiment 84

2-(1H-indoles-5-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (60mg, 0.20mmol, 1.00 equivalents), 1H-indoles-5-ylboronic acid (100mg, 0.62mmol, 3.05 equivalents), Pd (PPh ₃) ₄(23.6mg, 0.02mmol, 0.10 equivalent), K ₃PO ₄(174mg, 0.82mmol, 4.01 equivalents), 1,4-two

Alkane/H2O (4/1mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With methylene chloride (10: 1) residue is put on silicagel column.Through preparation HPLC with following condition (1#-Waters 2767-2) purifying crude product (60mg): post, SunFire Prep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 30%CH of CN ₃CN brought up to 55% with 8 minutes, kept 3 minutes 55%, brought up to 100% with 0.1 minute, 100% maintenance 0.9 minute); Detector, UV 220 and 254nm.Produce 25mg (33%) 2-(1H-indoles-5-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid red solid.

LC-MS：(ES，m/z)：361[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)δ11.305(s，1H)，8.254(s，1H)，8.124(s，1H)，7.923-7.920(d，J＝0.9Hz，2H)，7.668-7.662(m，1H)，7.530-7.501(d，J＝8.7Hz，1H)，7.439-7.421(t，J＝2.7Hz，1H)，6.559(s，1H)，4.263-4.175(m，1H)，2.704(s，3H)，1.013-0.990(d，J＝6.9Hz，6H).

Embodiment 85

3-(sec.-propyl (methyl) amino)-2-(4-(trifluoromethoxy) phenyl) quinoxaline-6-carboxylic acid

Step 1.3-(sec.-propyl (methyl) amino)-2-(4-(trifluoromethoxy) phenyl) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (200mg, 0.68mmol, 1.00 equivalents), 4-(trifluoromethoxy) phenyl-boron dihydroxide (280mg, 1.36mmol, 1.99 equivalents), Pd (PPh ₃) ₄(157mg, 0.14mmol, 0.20 equivalent), K ₃PO ₄(577mg, 2.73mmol, 4.01 equivalents), 1,4-two Alkane (4mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.Through this residue of purification by silica gel column chromatography with ethyl acetate/petroleum ether (1: 40).Produce 120mg (42%) 3-(sec.-propyl (methyl) amino)-2-(4-(trifluoromethoxy) phenyl) quinoxaline-6-carboxylate methyl ester yellow solid.

Step 2.3-(sec.-propyl (methyl) amino)-2-(4-(trifluoromethoxy) phenyl) quinoxaline-6-carboxylic acid

To be dissolved in 3-(sec.-propyl (methyl) amino)-2-(4-(trifluoromethoxy) phenyl) quinoxaline-6-carboxylate methyl ester (120mg of methyl alcohol (15mL); 0.29mmol; 1.00 equivalent) solution, sodium hydroxide (57mg, 1.43mmol, 4.98 equivalents), water (2mL) add in the 50mL round-bottomed flask.Gained solution stirred 2 hours in 50 ℃ of oil baths.Gained mixture vacuum concentration also dilutes with 20ml water.(2.5mol/L) is adjusted to 4-5 with this pH value of aqueous solution with hydrogenchloride.Filter and collect the gained solid.Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (100mg): post, SunFire Prep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 65%CH of CN ₃CN brought up to 85% with 8 minutes, brought up to 100% with 2 minutes); Detector, UV 220254nm.Produce 70mg (60%) 3-(sec.-propyl (methyl) amino)-2-(4-(trifluoromethoxy) phenyl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：406[M+H] ⁺

¹H?NMR(300MHz，DMSO，ppm)δ8.273(s，1H)，8.033-7.955(m，4H)，7.552-7.525(d，J＝8.1Hz，2H)，4.202-4.114(m，1H)，2.667(s，3H)，1.052-1.030(d，J＝6.6Hz，6H).

Embodiment 86

2-(4-cyano-phenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (150mg, 0.51mmol, 1.00 equivalents), 4-cyano-phenyl boric acid (150mg, 1.02mmol, 1.99 equivalents), Pd (PPh ₃) ₂Cl ₂(36mg, 0.05mmol, 0.10 equivalent), K ₃PO ₄(433mg, 2.04mmol, 3.99 equivalents), 1,4-two Alkane/H ₂O (4/1mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With methylene chloride (10: 1) residue is put on silicagel column.Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (100mg): post, SunFire Prep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 48%CH of CN ₃CN brought up to 68% with 8 minutes, brought up to 100% with 2 minutes); Detector, UV 220254nm.Produce 22mg (12%) 2-(4-cyano-phenyl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：347[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)δ13.242(s，1H)，8.276-8.273(d，J＝0.9Hz，2H)，8.052-7.931(m，6H)，4.211-4.123(m，1H)，2.647(s，3H)，1.060-1.038(d，J＝6.6Hz，6H).

Embodiment 87

3-(sec.-propyl (methyl) amino)-2-(pyridin-4-yl) quinoxaline-6-carboxylic acid

Step 1.3-(sec.-propyl (methyl) amino)-2-(pyridin-4-yl) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (150mg, 0.51mmol, 1.00 equivalents), pyridin-4-yl boric acid (124.5mg, 1.02mmol, 1.99 equivalents), Pd (PPh ₃) ₄(59mg, 0.05mmol, 0.10 equivalent), K ₃PO ₄(433mg, 2.04mmol), 1,4-two

Alkane (4mL) adds in the 10-mL ST.In 50 ℃ of oil baths of the solution that obtains under nitrogen atmosphere stirred overnight.The mixture of vacuum concentration gained.Through purification by silica gel column chromatography residue with EA/PE (1: 40).Produce 50mg (29%) 3-(sec.-propyl (methyl) amino)-2-(pyridin-4-yl) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：337[M+H] ⁺

Step 2.3-(sec.-propyl (methyl) amino)-2-(pyridin-4-yl) quinoxaline-6-carboxylic acid

To be dissolved in 3-(sec.-propyl (methyl) amino)-2-(pyridin-4-yl) quinoxaline-6-carboxylate methyl ester (50mg in the methyl alcohol (15mL); 0.15mmol; 1.00 equivalent) solution, sodium hydroxide (30mg, 0.75mmol, 5.04 equivalents), water (2mL) add in the 10mL ST.Gained solution stirred 2 hours in 50 ℃ of oil baths.Gained mixture vacuum concentration also dilutes with 20ml water.(2mol/L) is adjusted to 4-5 with this pH value of aqueous solution with hydrogenchloride.Filter and collect the gained solid.Produce 22mg (44%) 3-(sec.-propyl (methyl) amino)-2-(pyridin-4-yl) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：323[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)δ8.791-8.771(d，J＝6.0Hz，2H)，8.279-8.276(d，J＝0.9Hz，1H)，8.007-7.938(m，2H)，7.870-7.849(d，J＝6.3Hz，2H)，4.250-4.162(m，1H)，2.657(s，3H)，1.081-1.059(d，J＝6.6Hz，6H).

Embodiment 88

2-(H-imidazoles [1,2-a] pyridine-6-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (70mg, 0.24mmol, 1.00 equivalents), H-imidazo [1,2-a] pyridine-6-ylboronic acid (59mg, 0.36mmol, 1.53 equivalents), Pd (PPh ₃) ₄(28mg, 0.02mmol, 0.10 equivalent), K ₃PO ₄(200mg, 0.94mmol, 3.96 equivalents), 1,4-two

Alkane/H ₂O (4/1mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.Through this residue of purification by silica gel column chromatography with methylene chloride (30: 1).Through preparation HPLC with following condition (1#-Waters 2767-5) purifying gained crude product (80mg): post, SunFire Prep C18,19*150mm 5um; Moving phase contains 0.05%TFA and CH ₃Water (the 15%CH of CN ₃CN brought up to 37% with 9 minutes, brought up to 100% with 1 minute, was reduced to 15% with 1 minute); Detector, uv 254nm.Produce 26mg (30%) 2-(H-imidazo [1,2-a] pyridine-6-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：362[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)δ9.422(s，1H)，8.451(s，1H)，8.309(s，1H)，8.273-8.250(d，J＝6.9Hz，1H)，8.145(s，1H)，8.041-7.998(m，3H)，4.243-4.177(m，1H)，2.741(s，3H)，1.098-1.082(d，J＝4.8Hz，6H).

Embodiment 89

2-(cumarone-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

Step 1.2-(cumarone-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester

With 2-chloro-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (200mg, 0.68mmol, 1.00 equivalents), cumarone-2-ylboronic acid (220mg, 1.36mmol, 1.99 equivalents), Pd (PPh ₃) ₄(157mg, 0.14mmol, 0.20 equivalent), K ₃PO ₄(577mg, 2.73mmol, 4.01 equivalents), 1,4-two Alkane (4mL) adds in the 10-mL ST.Stirred overnight in 100 ℃ of oil baths of the solution that obtains.The mixture of vacuum concentration gained.With ethyl acetate/petroleum ether (1: 40) residue is put on silicagel column.Produce 160mg (63%) 2-(cumarone-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester yellow solid.

LC-MS：(ES，m/z)：376[M+H] ⁺

Step 2.2-(cumarone-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

To be dissolved in 2-(cumarone-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylate methyl ester (160mg of methyl alcohol (20mL); 0.43mmol; 1.00 equivalent) solution, sodium hydroxide (85mg, 2.12mmol, 4.99 equivalents), water (2mL) add in the 50mL round-bottomed flask.Gained solution stirred 2 hours in 50 ℃ of oil baths.The mixture of vacuum concentration gained.Gained solution dilutes with 20mL water.(2.5M) is adjusted to 4-5 with this pH value of aqueous solution with hydrogenchloride.Filter and collect the gained solid.Through preparation HPLC with following condition (1#-Waters 2767-1) purifying crude product (120mg): post, XbridgePrep Shield RP 18,5um, 19*150mm; Moving phase contains 0.05%TFA and CH ₃Water (the 58%CH of CN ₃CN brought up to 78% with 8 minutes, brought up to 100% with 2 minutes); Detector, UV 220254nm.Produce 70mg (45%) 2-(cumarone-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid yellow solid.

LC-MS：(ES，m/z)：362[M+H] ⁺

¹H-NMR(300MHz，DMSO，ppm)δ13.250(s，1H)，8.275-8.272(d，J＝0.9Hz，1H)，8.034-7.962(m，2H)，7.826-7.702(m，3H)，7.482-7.328(m，2H)，4.254-4.167(m，1H)，2.836(s，3H)，1.180-1.158(d，J＝6.6Hz，6H).

The modified version of scheme shown in following compound can pass through is usually accomplished.

Scheme IV

Embodiment 90

(S)-2-(4-fluorophenyl)-3-(2-methyl-4-(pyridine-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：444[M+H].

Embodiment 91

(S)-2-(4-fluorophenyl)-3-(pipecoline-1-yl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：366[M+H].

Embodiment 92

3-(cyclopropyl (methyl) amino)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：338[M+H].

Embodiment 93

(R)-2-(4-fluorophenyl)-3-(2-(methoxymethyl) tetramethyleneimine-1-yl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：382[M+H].

Embodiment 94

(S)-3-(2-methyl-4-(pyridine-2-yl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：426[M+H].

Embodiment 95

2-(benzo [d] [1,3] dioxo-5-yl)-3-(3,4-EEDQ-1 (2H)-yl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：426[M+H].

¹H-NMR(300MHz，CDCl ₃)：8.70(s，1H)，8.22(d，J＝8.6Hz，1H)，8.11(d，J＝8.6Hz，1H)，7.32(d，J＝8.4Hz，1H)，7.29(1H)，7.06(m，1H)，6.88(m，1H)，6.86-6.67(m，4H)，5.95(s，2H)，3.87(br?t，2H)，2.84(brt，2H)，2.09(br?t，2H).

Embodiment 96

3-(octahydro quinoline-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：388[M+H].

Embodiment 97

3-(sec.-propyl (methyl) amino)-2-(pyridin-3-yl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：323[M+H].

Embodiment 98

2-(furans-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：312[M+H].

Embodiment 99

3-(sec.-propyl (methyl) amino)-2-(quinoline-3-yl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：373[M+H].

Embodiment 100

3-(sec.-propyl (methyl) amino)-2-(4-morpholino phenyl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：407[M+H].

Embodiment 101

3-(1,1-diepoxy thio-morpholinyl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：402[M+H].

Embodiment 102

3-(1,1-diepoxy thio-morpholinyl)-2-phenyl quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：384[M+H].

Embodiment 103

2-(4-fluorophenyl)-3-(3-oxo piperazine-1-yl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：367[M+H].

Embodiment 104

2-(4-fluorophenyl)-3-(methyl (piperidin-4-yl) amino) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：331[M+H].

Embodiment 105

2-(4-fluorophenyl)-3-(methyl (tetrahydrochysene-2H-pyrans-4-yl) amino) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：382[M+H].

Embodiment 106

3-(cyclopentyl (methyl) amino)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：366[M+H].

Embodiment 107

3-(sec.-propyl (methyl) amino)-2-(5-thiotolene-2-yl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：342[M+H].

Embodiment 108

3-(sec.-propyl (methyl) amino)-2-(thiophene-2-yl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：328[M+H].

Embodiment 109

3-(sec.-propyl (methyl) amino)-2-(6-methoxypyridine-3-yl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：353[M+H].

Embodiment 110

2-(furans-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：312[M+H].

Embodiment 111

2-(4-fluorophenyl)-3-(4-(N-methyl kharophen) piperidines-1-yl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：423[M+H].

Embodiment 112

2-(4-fluorophenyl)-3-(4-methyl-3-oxo piperazine-1-yl) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：381[M+H].

Embodiment 113

2-(1H-indoles-6-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：361[M+H].

Embodiment 114

2-(1H-indoles-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

LC-MS：(ES，m/z)：361[M+H].

Usually adopt the compound below means known in the art and the method for preparing.Estimate to have the activity that is similar to the compound that has prepared in the foregoing description after these compound.

2-phenyl-3-(2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) quinoxaline-6-carboxylic acid

2-(4-fluorophenyl)-3-(2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) quinoxaline-6-carboxylic acid

(S)-3-(second month in a season-butyl (methyl) amino)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid

3-(second month in a season-butyl (methyl) amino)-2-(furans-3-yl) quinoxaline-6-carboxylic acid

3-(sec.-propyl (methyl) amino)-2-(1H-pyrazoles-4-yl) quinoxaline-6-carboxylic acid

2-(1H-indazole-6-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

3-(sec.-propyl (methyl) amino)-2-(1-methyl isophthalic acid H-indazole-6-yl) quinoxaline-6-carboxylic acid

2-(1-(tert-butoxycarbonyl)-1H-indoles-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

2-(1-(tert-butoxycarbonyl)-5-methoxyl group-1H-indoles-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

3-(sec.-propyl (methyl) amino)-2-(5-methoxyl group-1H-indoles-2-yl) quinoxaline-6-carboxylic acid

2-(5-fluoro-1H-indoles-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

2-(5-bromopyridine-3-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

2-(1H-indazole-5-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

3-(sec.-propyl (methyl) amino)-2-(3-(trifluoromethyl)-1H-pyrazoles-4-yl) quinoxaline-6-carboxylic acid

2-(6-(tert-butoxycarbonyl is amino) pyridin-3-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

2-(5-fluorine pyridine-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

3-(sec.-propyl (methyl) amino)-2-(5-(trifluoromethyl) pyridine-2-yl) quinoxaline-6-carboxylic acid

3-(sec.-propyl (methyl) amino)-2-(6-(trifluoromethyl) pyridin-3-yl) quinoxaline-6-carboxylic acid

2-(5-cyanopyridine-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

3-(sec.-propyl (methyl) amino)-2-(6-(tetramethyleneimine-1-yl) pyridin-3-yl) quinoxaline-6-carboxylic acid

2-(6-fluorine pyridin-3-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

(S)-2-(cumarone-2-yl)-3-(2-methylpyrrolidin-1-yl) quinoxaline-6-carboxylic acid

2-(cumarone-2-yl)-3-(cyclopropyl (methyl) amino) quinoxaline-6-carboxylic acid

2-(5-fluorobenzene and furans-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

2-(5-chlorobenzene and furans-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid

2-(cumarone-2-yl)-3-(second month in a season-butyl (methyl) amino) quinoxaline-6-carboxylic acid

Compound is set forth in following test as the activity of PASK adjusting control agent among the embodiment 1-114.Above-mentioned other compounds of estimating not prepare as yet and/or test also have activity in these are tested.

The active biochemical test of hPASK

The kinase whose luminous test of PAS

The luminous kinase assay of kinases-Glo (Pu Luomaige (Promega)) is adopted in the hPASK activity test of purifying, residual ATP amount in the solution behind the quantitative kinase reaction of this test ability.This test is carried out through adding the kinases-Glo reagent (Pu Luomaige, catalogue #V3771) that equates with the volume of solution in the complete kinase reaction hole on 96 well plate format.Kinases-Glo reagent contains luciferase and its substrate.Detect luminous after adding in the kinase reaction.Luminous being directly proportional of detecting in residual A TP amount and each hole in the solution when kinases-Glo Plus adds is inversely proportional to kinase activity.

To add from the purifying hPASK (.02 μ g) of insect cell and contain 40mM HEPES (pH 7.0), 100mM KCl, 5mM MgCl ₂, in 1mM DTT and the proteic 50 μ L reaction mixtures of 1 μ g MBP.Add to suppress compound then and mixture was hatched 10 minutes in 25 ℃, add 5 μ L ATP (with desired concn) then.Be reflected at 25 ℃ and carried out 1 hour, add 50 μ L kinases-Glo reagent then.Kinases-adding of Glo reagent detects luminous immediately after 10 minutes.

The result is listed in the table below 1.

Table 1.

The test of PASK ATP radiological cheanistry

Will be from purifying PASK (the UniProt #Q96RG2 of insect cell; What people's N-terminal GST mark construct of recombinating, residue 879-1323) (final concentration 5nM) added prepared fresh contains 20mM HEPES (pH 7.5), 10mM MgCl ₂, 1mM EGTA, 0.02%Brij35,0.02mg/ml BSA, 0.1mM Na ₃VO ₄, 2mM DTT, the alkali reaction damping fluid (Base Reaction Buffer) of 1%DMSO and MBP (final 20 μ M).The detection compound that will be dissolved in DMSO then adds this mixture, sends then ³³P-ATP (final specific activity is 0.01 μ Ci/ μ l) is to start reaction.This kinase reaction incubated at room 120 minutes.Complete reaction mixture cleans on P81 phosphorylated cotton paper, in 75mM phosphoric acid, cleans 3 times each 10 minutes and in methyl alcohol, cleans once, dry then and scintillation counting

This test-results is listed in the table below 2.NT representes that this compound does not detect.

Table 2.

The kinase whose FRET test of PAS

The purpose of FRET test is to confirm that detection compound is to the kinase whose inhibition ability of target.Phosphate substrate amount detects kinase activity in the solution after this test platform provides even screening method through quantitative kinase reaction.

When having kinases and ATP, the Ulight peptide is by phosphorylation and by anti-phosphate substrate antibody capture, said antibody make Eu intercalating agent donor and Ulight acceptor dye closely near.When 340nm excited, the Eu intercalating agent was transferred to its energy in the Ulight dyestuff, produced the fluorescent emission at 665nm place.

Kinases titration when realizing 1mM ATP through following testing program.With reaction buffer to the whole continuous three times of dilutions of plate PASK (hero company (Invitrogen)) after; 5 μ l kinase dilution liquid and 5 μ l substrates/ATP mixture are added in the hole of dull and stereotyped (Optiplate)-384 of white optical (Pa Jin Elmer Co., Ltd (PerkinElmer)).The inclusion incubated at room of said plate 1 hour.Add 5 μ l and stop solution and come termination reaction through detect hole to each, mix being incorporated in incubated at room 10 minutes then.Add 5 μ l and detect mixture (the detection antibody that in detecting damping fluid, dilutes); The inclusion of mixing said plate room temperature lucifuge was then hatched 1 hour.Signal (665nm/615nm) under the record TR-FRET pattern.The result is drawn to calculate EC ₅₀

Carry out kinases EC with following method ₅₀ATP titration during concentration is to confirm the apparent Km of ATP.After ATP (hero company (Invitrogen)) serial dilution, 5 μ l ATP diluents and 5 μ l substrates/kinases mixture are added in the hole of dull and stereotyped (Optiplate)-384 of white optical (Pa Jin Elmer Co., Ltd).The inclusion incubated at room of said plate 1 hour.Add 5 μ l and stop solution and come termination reaction through detect hole to each, mix being incorporated in incubated at room 10 minutes then.Add 5 μ l and detect mixture (the detection antibody that in detecting damping fluid, dilutes); The inclusion of mixing said plate room temperature lucifuge was then hatched 1 hour.Signal (665nm/615nm) under the record TR-FRET pattern.The result is drawn to calculate EC ₅₀As the apparent Km of said ATP.

Carry out screening compound through following method.Continue the detection compound 10mM storage liquid that preparation in 1 hour is dissolved in DMSO through the detection compound room temperature being dissolved in DMSO, exported supersound process 8 minutes with 100% then.If compound is inappropriate for this condition, then its dilution is 3mM.Preparation contains 10mM MgCl ₂, 50mM HEPES, 1mM EGTA, 0.01%TWEEN-20,2mM DTT the kinase reaction damping fluid.Use Freedom EVO200 with 4 * test final concentration

Distribution system prepares the serial dilutions of said detection compound: 12 * 10 ^-5M, 4 * 10 ^-5M, 1.33 * 10 ^-5M, 4.44 * 10 ^-6M, 1.48 * 10 ^-6M, 4.92 * 10 ^-7M, 1.65 * 10 ^-7M, 5.48 * 10 ^-7M, 1.82 * 10 ^-8M, 6.09 * 10 ^-9, 2.03 * 10 ^-9M.With Freedom EVO200

distribution system detection compound (2.5 μ l, 4 * test final concentration) is added in the hand-hole.2.5 μ l positive compounds are added test holes as positive control, and 2.5 μ l DMSO adding test holes contrasts as supporting agent.In reaction buffer, prepare kinase solution with 2 * test final concentration.Kinase solution (5 μ l) is added in each hole of said test board.In the kinase reaction damping fluid, prepare substrate and ATP solution with 4 * test final concentration.Begin kinase reaction through in each hole of said test board, adding 2.5 μ l substrate+ATP mixed solutions.Said plate jolts on the device at plate and mixes; Cover then and jolt lucifuge and reacted 2 hours in 25 ℃ of nothings.Add 5 μ l and stop solution and come termination reaction through detect hole to each, mix being incorporated in the room temperature lucifuge and hatching 10 minutes then.Add 5 μ l and detect mixture (the detection antibody that in detecting damping fluid, dilutes); The inclusion of mixing said plate room temperature lucifuge was then hatched 1 hour.Signal (665nm/615nm) under the record TR-FRET pattern.

The result is listed in the table below 3.

Table 3.

In vivo tests

The foregoing description 57 disclosed selection compounds (" motif compound ") detect in the dyslipidemia of two kinds of models.Although this compound is a specificity PASK suppressor factor, predict its PASK-that can in mouse high lipid diet model and the high fructose meals of rat model, regenerate/-the important phenotypic characteristic of mouse (31).Following all numerical value that provide are the average of treatment group.

Mouse high lipid diet model

The standard model of people's hyperlipemia and insulin resistance is the feeding high fat diet mouse of several weeks (31,33).In addition, because the synthetic regulation and control that receive food consumption of known liver lipid, the fasting of Horton etc. (32)/the feeding circulation is included in the said chronic high fat diet model again.In this model, estimate said compound as the reagent of rebuilding insulin sensitivity and reduce fat.Give the chronic high fat diet of mouse feeding with the mock standard western diet, it raises from the heat in high fat and the glucide picked-up.This model brings out obesity, insulin insensitivity and raise serum lipid and SUV with similar meals model, uses these models to comprise the mouse and the rat model of hyperlipidaemia, type ii diabetes, atherosclerosis, obesity, cardiovascular and hepatic diseases as people's pathology.These models have been used as good effect predictor in people's clinical experiment (PPAR and FXR agonist).

Method Buddhist nun's ester X-acceptor (FXR) is part activated transcription factor and is the member of nuclear receptor superfamily.Shown that this receptor plays an important role in control bile acide homeostasis, lipoprotein and glucose metabolism, liver regeneration, enterobacteria growth with to hepatotoxin answer party mask.WAY-362450 be the agonist of FXR and shown its in several hyperlipemia models, reduce serum triglyceride and SUV and in the mouse Atherosclerosis Model protection avoid taking place the atherosclerotic patch and form; And protection avoids liver inflammation and fibrosis (33 in the mouse model of nonalcoholic fatty liver disease; 34; 35,36).Though the mechanism of action of FXR agonist suppresses obviously different with PASK, WAY-362450 has been used as positive control compound, the similar inhibition of lipid metabolism of useful variation of glucogenic physiology and PASK.In these in vivo tests, WAY-362450 is as control compound, and meeting indication like this.

Table 4 shows research and design.

Table 4.

Group	Test item	Dosage level (mg/kg)	Dose concentration (mg/mL)
				1	Supporting agent	0	0
2	Motif compound	30	3
				3	Motif compound	100	10
4	Contrast	30	3

Male C57B16 mouse is available from Jackson (Jackson) laboratory and used high fat diet (60% kilocalorie of fat) 8 weeks of feeding.The high fat diet that feeding was identical during mouse arrived the back and studies (research diet D12492).All mouse through every day oral raise by force 30 or motif compound (WAY-362450) or the supporting agent of the motif compound of 100mg/kg, 30mg/kg handled 3 days.The last day, each is organized 10 animals and begins fasting in 24 hours and put to death (fasting group 1a, 2a, 3a, 4a) then.Perhaps, each organizes the fasting in 24 hours of 10 animals experience, and identical high fat diet in the 12 hours feeding period again that arbitrarily can get is put to death (feeding group 1b, 2b, 3b, 4b again) then then.

Experimental program begins and last monitoring body weight.After accomplishing the feeding condition of said fasting or fasting/again, intraperitoneal gives the avertin anesthesia mouse.Gather whole blood and put to death mouse through cardiac puncture with cervical dislocation.Surgical operation is gathered liver, weighs and freezing in liquid nitrogen immediately.Place the Li-heparin to handle pipe, centrifugal collection blood plasma and FP blood.

Glucose, Regular Insulin, triglyceride level and SUV through standard colorimetric test analysed for plasma.Grinding refrigerated liver sample also extracts in ethanol property KOH, analyzes liver tg and SUV then.

After accomplishing the circulation of the feeding of said dosage and said fasting/again, the heavy 29.2g of the animal that supporting agent is handled.In the dosage dependence mode, with motif compound processing the minimizing respectively body weight 2.7% and 5.1% of 30mg/kg or 100mg/kg.In the feeding group of fasting/again, the control compound of 30mg/kg (WAY-362450) also reduces by 6.5% than the body weight of supporting agent group.The supporting agent of only fasting in addition, (not having feeding again) is handled mouse heavy 27.3g when research is accomplished.Motif compound also reduces only fasting the weight of animals 1.8% and 5.1%, and is similar with the dose-dependently weight loss of fasting and feeding animals again.Control compound reduces only fasting the weight of animals 4% than supporting agent fasting group.

Fasting or fasting in that supporting agent, motif compound or control compound are handled are measured liver weight in the feeding mouse again.The average finally liver weight of fasting that supporting agent is handled and feeding mouse again is respectively 1.2g and 0.9g in feeding group of fasting/again and only fasting group.30 cause the descend trend of about 7-9% of the liver weight of dose-dependently with the motif compound of 100mg/kg.The control compound of 30mg/kg is handled identical with the motif compound of same dose to the influence of liver weight.

In the fasting group with again in the feeding group, motif compound is compared the relevant reduction that also causes plasma glucose and insulin level with the mouse that supporting agent is handled.These influences are similar or bigger with the influence that the control compound processing is produced.The plasma glucose levels of handling mouse through complete fasting and feeding round-robin supporting agent again is 104mg/dl, and said motif compound reduction glucose 21% at most under maximum dose level (100mg/kg) condition.Control compound increases plasma glucose 7.6%.In the only fasting group mouse, the average circulating plasma glucose concn of the mouse that supporting agent is handled is that 116mg/dl and said motif compound reduce glucose 30% and 43% with the relevant mode of dosage.Said control compound causes 19% decline in the fasting mouse.

Compare with supporting agent contrast (2.32 μ IU/ml), can dose-dependently ground reduce fasting and the plasma insulin concentration of feeding mouse when 100mg/kg (30 and be 10% and 28%) again through handling with motif compound.Handle mouse with supporting agent and compare, control compound handle through fasting and again in the feeding round-robin mouse Regular Insulin also reduce by 22%.In fasting mouse only, final plasma insulin concentration is 2.12 μ IU/ml, and this control level is reduced maximum 26% and reduced by 39% by control compound (30mg/kg) by motif compound (30 and 100mg/kg).

In high fat feeding mouse model, the oral dosage of every day 30 and 100mg/kg motif compound also causes fasting and the relevant body weight reduction of dosage in the as fed again for three days on end.In addition, said PASK suppressor factor brings out concentration dependent liver weight and descends in fasting state, the similar trend in this and the said as fed again.These of body weight and liver weight change with to be exposed to variation that said control compound produces similar or equate.In addition, said motif compound is handled plasma glucose and the insulin level decline that produces dose-dependently.In fasting with notice these influences again in the as fed and expose the influence that causes quite or bigger with control compound.The reduction of body weight, liver weight, plasma glucose and insulin concentration shows the Regular Insulin again sensitization (resensitization) relevant with the type ii diabetes phenotype and utilizes.

The high fructose model of feeding rat of fasting/again

Another standard model of people's hyperlipemia and insulin resistance is the high fructose diet of the feeding rat (33) of several weeks.In addition, because the synthetic regulation and control that receive food consumption of known liver lipid, the fasting of Horton etc. (32)/the feeding circulation is included in the said chronic high fructose diet model again.In this model, estimate above-mentioned disclosed compound as the reagent of rebuilding insulin sensitivity and reduce fat.

Table 5 shows research and design.

Table 5.

Eight all big male SD (Sprague Dawley) rats are available from breathing out human relations (Harlan) company.The rat of weight 200-225 arrives the back and divides into groups according to the details of table 2, and places high fructose diet (60% kilocalorie of fructose that arbitrarily can get immediately; Open source diet #D00111301) continued for 3 weeks in.In last week of the high fructose diet of feeding, the control compound administered through oral of the motif compound of supporting agent (5% Suolu appropriate (solutol), 8% beta-cyclodextrin), 30mg/kg or 100mg/kg or 30mg/kg raised by force give said rat once a day and continue 7 days.The last day, all animals carry out fasting in 12 hours, are 12 hours of the high fructose diet that arbitrarily can get feeding periods more then.

Monitor body weight in the whole experimental program.After accomplishing the feeding condition of said fasting or fasting/again, intraperitoneal gives the avertin anesthesia rat.Gather whole blood and put to death rat through cardiac puncture with cervical dislocation.Surgical operation is gathered liver, weighs and freezing in liquid nitrogen immediately.Place the Li-heparin to handle pipe, centrifugal collection blood plasma and FP blood.

Glucose, Regular Insulin, triglyceride level and SUV through standard colorimetric test analysed for plasma.

As shown in Figure 1, in 7 days the drug-treated process, the body weight of the more said supporting agent control group of said control compound treatment group significantly increases.The rat of handling with the 30mg/kg motif compound shows appropriate body weight gain with respect to the supporting agent group, and reduces with respect to the body weight that the supporting agent group shows appropriateness with the rat that the 100mg/kg motif compound is handled.

Measure the liver weight of the high fructose diet rat of handling with said motif compound and control compound.Liver weight increases about 2g on a small quantity in the rat that control compound is handled, and the liver weight of the rat of motif compound processing only has the relevant reduction trend of dosage slightly.Observe the maximum reduction about 4% of liver weight during 100mg/kg motif compound dosage in the rat of high fructose model.On the other hand, control compound increases liver weight about 15% in these animals.

Said motif compound is compared supporting agent and is handled the dosage correlation reduction that rat also causes plasma glucose and insulin level.These influences are similar or bigger with the influence that the control compound processing is produced.Fasting and again after the feeding circulation, average blood plasma glucose and insulin concentration that the supporting agent of high fructose diet is handled rat are 205mg/dl and 42.1 μ IU/ml.Handle with supporting agent and to compare, the plasma glucose that is exposed in said motif compound 30 and the 100mg/kg treatment group 7 days rat descends 21.5% and 26.3% respectively.Said control compound does not change plasma glucose concentration.Expose through motif compound, insulin level reduces by 15.4% and 31.4%, and the insulin level of said control compound rat reduces by 63.2%.

Compare the clear and definite dose-dependently decline of motif compound processing causing plasma triglyceride and the downtrending a little of plasma cholesterol with the supporting agent control rats.Fasting and again in the supporting agent rat of the high fructose diet of feeding triglyceride level and cholesterol levels be respectively 387mg/dl and 69mg/dl.Motif compound described in the 30mg/kg group causes that triglyceride level reduction by 25.1% and 100mg/kg reduce by 54.3% in organizing.Said control compound is compared with the supporting agent rat and is also reduced plasma triglyceride 68%.Cholesterol concentration descends 5.7 and 10% in 30 rats of handling with the 100mg/kg motif compound.Yet the control compound of 30mg/kg is handled and is improved plasma cholesterol 17%.

Every day, orally give 30 continued 7 days with the 100mg/kg motif compound, caused that fasting/the dosage correlation body weight of the high fructose diet rat of feeding reduces again.In addition, said PASK suppressor factor brings out the downtrending that said rats'liver weight has concentration to rely on slightly.The processing of said control compound causes the increase of the body weight and the liver weight of this model.Said motif compound is handled and is produced dose-dependent plasma glucose and insulin level decline.In the high fructose feeding rat, said motif compound significantly reduces plasma triglyceride concentration and reduces blood plasma cholesterol level slightly with the relevant mode of dosage.All these metabolic effect of said motif compound and control compound expose caused influence quite or bigger.The reduction of body weight, liver weight, plasma glucose and insulin concentration shows the Regular Insulin relevant with the type ii diabetes phenotype sensitization and utilization again.The dosage correlation reduction of plasma triglyceride and SUV shows the hyperlipidemia overview.

Through above explanation, those skilled in the art can easily know principal character of the present invention, and can be under the situation that does not deviate from spirit and scope of the invention, and the present invention is carried out various changes and improvement so that it is suitable for various application and condition.

Claims

1. compound in structural formula I:

Or its pharmacy acceptable salt, ester or its prodrug, it is characterized in that:

X ₁And X ₂Be selected from CH and N independently of one another;

R ₅And R ₆Be selected from hydrogen, C independently of one another ₁-C ₆Alkyl, C ₁-C ₆Thiazolinyl, C ₁-C ₆Alkynyl, C ₁-C ₇Naphthenic base, C ₁-C ₇Heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, wherein any group all can be optionally substituted; Or R ₅And R ₆Can form Heterocyclylalkyl or heteroaryl together, wherein any group all can be optionally substituted;

M and n are the integer of 0-2 independently of one another.

2. compound as claimed in claim 1 is characterized in that X ₁And X ₂Be N.

3. compound as claimed in claim 2 is characterized in that R ₄Be COOR ₇

4. compound as claimed in claim 3 is characterized in that,

5. compound as claimed in claim 3 is characterized in that,

6. compound as claimed in claim 3 is characterized in that R ₁₈And R ₁₉Choose replacement wantonly with one or more substituting groups that are selected from down group: hydrogen, halogen, alkoxyl group, halogenated alkoxy, alkyl and amino.

7. compound as claimed in claim 3 is characterized in that, said compound has structural formula II:

Or its salt, ester or prodrug, in the formula:

8. compound as claimed in claim 7 is characterized in that, said compound has structural formula II I:

Or its salt, ester or prodrug, in the formula:

R ₃Be selected from hydrogen and hydroxyl;

X ₄Be selected from CH, N and O.

9. compound as claimed in claim 3 is characterized in that, said compound has structural formula IV:

Or its salt, ester or prodrug, in the formula:

Rz is selected from OH, NR ₈, R ₉, NR ₈OR ₉

10. compound as claimed in claim 9 is characterized in that,

11. compound as claimed in claim 9 is characterized in that, R ₅And R ₆Be C independently ₁-C ₆Alkyl.

12. compound as claimed in claim 9 is characterized in that, R ₃Be hydrogen.

13. compound as claimed in claim 12 is characterized in that, R ₅And R ₆Be C independently ₁-C ₆Alkyl.

14. compound as claimed in claim 9 is characterized in that, said compound has structural formula V:

Or its salt, ester or prodrug, in the formula:

R ₃Be selected from hydrogen and hydroxyl;

R ₁₇Be selected from hydrogen and C ₁-C ₆Alkyl; With

X ₃Be selected from CH, N and O.

15. compound as claimed in claim 9 is characterized in that, said compound has structural formula VI:

Or its salt, ester or prodrug, in the formula:

Rz is selected from OH, NR ₈, R ₉, NR ₈OR ₉

R ₃Be selected from hydrogen and hydroxyl;

N is the integer of 0-3; And

X ₃Be selected from CH ₂, NR ₁₂, S, SO ₂And O.

16. compound as claimed in claim 1 is characterized in that, said compound is as medicine.

17. compound as claimed in claim 1 is characterized in that, said compound is used to prepare medicine, and said medicine is used to prevent or treats can be through suppressing disease or the illness that PASK improves.

18. compound as claimed in claim 9 is characterized in that, said compound is used to prepare medicine, and said medicine is used to prevent or treats can be through suppressing disease or the illness that PASK improves.

19. compound that is selected from down group

3-(4-N-METHYL PIPERAZINE-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

2-phenyl-3-(piperazine-1-yl) quinoxaline-6-carboxylic acid,

2-phenyl-3-(4-phenylpiperazine-1-yl) quinoxaline-6-carboxylic acid,

2-phenyl-3-(piperidines-1-yl) quinoxaline-6-carboxylic acid,

2-phenyl-3-(4-Phenylpiperidine-1-yl) quinoxaline-6-carboxylic acid,

3-(azepan-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-morpholino-2-phenyl quinoxaline-6-carboxylic acid,

3-(isopropylamino)-2-phenyl quinoxaline-6-carboxylic acid,

2-phenyl-3-(4-(quinoline-2-yl) piperazine-1-yl) quinoxaline-6-carboxylic acid,

2-(azepan-1-yl)-3-phenyl quinoxaline-6-carboxylic acid,

3-phenyl-2-(piperidines-1-yl) quinoxaline-6-carboxylic acid,

2, two (4-Phenylpiperidine-1-yl) quinoxalines-6-carboxylic acid of 3-,

2, two (4-p-methoxy-phenyl)-6-(1H-tetrazolium-5-yl) quinoxalines of 3-,

3-(4-(methylsulfonyl) piperazine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(diethylamino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(N-methylmethane-5-ylsulfonylamino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(3,4-dihydro-isoquinoline-2 (1H)-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(benzene ethylamino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(methyl (styroyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(hexamethylene is amino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(pipecoline-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(cyclopropyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

(R)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

(S)-3-(3-hydroxyl pyrrolidine-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(3-methylmorpholine generation)-2-phenyl quinoxaline-6-carboxylic acid,

(S)-3-(2-methylpyrrolidin-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

(R)-3-(methyl (1-phenylethyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

(S)-3-(methyl (1-phenylethyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

3-(1H-indoles-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(6-methoxyl group-3,4-EEDQ-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(indoline-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(2; 3-dihydrobenzo [b] [1; 4]

piperazine-4-yl)-2-phenyl quinoxaline-6-carboxylic acid

3-(cyclopentyl (methyl) amino)-2-phenyl quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(piperidines-1-yl) quinoxaline-6-butyl carboxylate,

3-(azepan-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid,

3-(3,3-lupetidine-1-yl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(3-methyl piperidine-1-yl) quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(pyridin-4-yl) quinoxaline-6-carboxylic acid,

2-(H-imidazo [1,2-a] pyridine-6-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

2-(cumarone-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

(S)-2-(4-fluorophenyl)-3-(pipecoline-1-yl) quinoxaline-6-carboxylic acid,

3-(octahydro quinoline-1 (2H)-yl)-2-phenyl quinoxaline-6-carboxylic acid,

3-(sec.-propyl (methyl) amino)-2-(pyridin-3-yl) quinoxaline-6-carboxylic acid,

2-(furans-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(1,1 diepoxy thio-morpholinyl)-2-(4-fluorophenyl) quinoxaline-6-carboxylic acid,

3-(1,1 diepoxy thio-morpholinyl)-2-phenyl quinoxaline-6-carboxylic acid,

2-(4-fluorophenyl)-3-(3-oxo piperazine-1-yl) quinoxaline-6-carboxylic acid,

2-(furans-2-yl)-3-(sec.-propyl (methyl) amino) quinoxaline-6-carboxylic acid,

3-(4-kharophen piperidines-1-yl)-2-phenyl quinoxaline-6-carboxylic acid,

2-(cumarone-2-yl)-3-(cyclopropyl (methyl) amino) quinoxaline-6-carboxylic acid,

20. compound as claimed in claim 19 is characterized in that, said compound is 3-(4-fluorophenyl)-2-(4-(4-p-methoxy-phenyl) piperidines-1-yl) quinoxaline-6-carboxylic acid.

21. a pharmaceutical composition, it comprises like described compound of claim 1-20 and pharmaceutically acceptable carrier.

22. a method that suppresses PASK, said method comprise with contacting PASK like the described compound of claim 1-20.

23. a method of treating disease, said method comprise the treatment significant quantity needed its patient like the described compound of claim 1-20.

24. method as claimed in claim 23 is characterized in that, said disease is selected from cancer and metabolic trouble.

25. method as claimed in claim 23 is characterized in that, said disease is a metabolic trouble.

26. method as claimed in claim 25 is characterized in that, said metabolic trouble is selected from metabolic syndrome, mellitus, dyslipidemia, fatty liver disease, nonalcoholic fatty liver disease, obesity and insulin resistance.

27. method as claimed in claim 26 is characterized in that, said mellitus are type ii diabetes.

28. method as claimed in claim 26 is characterized in that, said dyslipidemia is a hyperlipidaemia.

29. method that in the patient, realizes effect; Said method comprise with the treatment significant quantity give the patient like each described compound among the claim 1-20, wherein said effect is selected from down group: triglyceride level reduces, SUV reduction and HbA1 c reduction.

30. method as claimed in claim 29 is characterized in that, said SUV is selected from LDL and VLDL SUV.

31. method as claimed in claim 29 is characterized in that, said triglyceride level is selected from plasma triglyceride and liver triglyceride level.

32. comprising, a method of treating the disease of PASK mediation, said method give:

C. treat the compound as claimed in claim 1 of significant quantity; With

D. another kind of therapeutical agent.